Theoretical and Experimental Investigation of the Effects of Some Molecules Containing Piperidine Ring on Glutathione S-Transferase and Cholinesterase Enzymes

Yıl 2024, Cilt: 14 Sayı: 2, 812 - 821, 01.06.2024

Fikret Türkan , Kübra Akil

https://doi.org/10.21597/jist.1470721

Öz

In this study, the inhibition effects of aniline molecules of 1-(2-Furylmethyl) piperidine-3-carboxylic acid hydrochloride (molecule 1), and 3-Chloro-4-(3,5-dimethyl-1-piperidinyl) aniline (molecule 2), which contain piperidine ring, on the enzymes of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and glutathione s-transferase (GST) were investigated. The studies of IC50 and Ki were performed for the inhibitors. All the molecules were found to be good inhibitors for the three enzymes. Molecule 2 was detected to be an effective inhibitory with Ki values of 2.9987±0.2555 for the AChE enzyme and 1.9301±0.2563 for the BChE enzyme. Molecule 1 was found to be another effective molecule with a Ki value of 4.217±0.3759 for the GST enzyme. Ethacrynic acid (EA) and tacrine (TAC) were used as positive inhibitions for enzymes of GST and cholinesterases, respectively. The studied molecules were detected to be more effective compared to the standard compounds. Additionally, enzyme inhibitor interaction was examined theoretically by molecular docking.

Anahtar Kelimeler

Inhibition, Molecular docking, Piperidine, Cholinesterase, Glutathione S-transferase

Teşekkür

Çalışmanın deneysel kısmı Iğdır Üniversitesi Araştırma ve Uygulama Laboratuvarında (ALUM) gerçekleştirilmiştir. Çalışma İmkanı bize sağlayan ALUM yönetimine teşekkür ederim. Ayrıca çalışmanın teorik kısmında bize yardımcı olan Doç. Dr. Adnan ÇETİN hocamıza çok teşekkür ederim.

Piperidin Halkası İçeren Bazı Moleküllerin Glutatyon S-Transferaz ve Kolinesteraz Enzimleri Üzerine Etkilerinin Teorik ve Deneysel Olarak İncelenmesi

Öz

Bu çalışmadaş bünyesinde piperidin halkası bulunduran 1-(2-Furylmethyl) piperidine-3-carboxylic acidhydrochloride (molekül 1), ve 3-Chloro-4-(3,5-dimethyl-1-piperidinyl) aniline (molekül 2) moleküllerinin asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BChE) ve glutatyon s-transferaz (GST) enzimleri için inhibisyon etkileri incelendi. İnhibitörler için hem IC50 hem de Ki çalışmaları yapıldı. Tüm moleküllerin her üç enzim için de iyi birer inhibitör olduğu bulundu. 2.9987±0.2555 Ki değeriyle AChE enzimi için, 1.9301±0.2563 Ki değeriyle de BChE enzimleri için molekül 2’ nin etkin inhibitör olduğu bulundu. GST enzimi için ise en etkili inhibitör 4.217±0.3759 değeriyle molekül 1 tespit edilmiştir. Çalışmada etakrinik asit (EA) GST enziminin, takrin (TAC) ise kolinesteraz enzimlerinin pozitif inhibitörü olarak kullanıldı. Moleküllerin standartlardan daha etkin oldukları ve sonucuna ulaşıldı. Ayrıca moleküler doking yapılarak enzim inhibitör etkileşimi teorik olarak incelendi

Anahtar Kelimeler

İnhibisyon, Moleküler doking, Piperidin, Glutatyon S-transferaz, Kolinesteraz

Kaynakça

• Abrunhosa-Thomas, I., Plas, A., Vogrig, A., Kandepedu, N., Chalard, P., ve Troin, Y. (2013). Access to 2, 6-disubstituted piperidines: control of the diastereoselectivity, scope, and limitations. applications to the stereoselective synthesis of (−)-solenopsine A and alkaloid (+)-241D. The Journal of Organic Chemistry, 78(6), 2511-2526.
• Allderdice, P., Gardner, H., Galutira, D., Lockridge, O., Ladu, B. N., ve McAlpine, P. (1991). The cloned butyrylcholinesterase (BCHE) gene maps to a single chromosome site, 3q26. Genomics, 11(2), 452-454.
• Aydın, T., Yurtvermez, B., Şentürk, M., Kazaz, C., ve Çakır, A. (2019). Inhibitory effects of metabolites isolated from Artemisia dracunculus L. against the human carbonic anhydrase I (hCA I) and II (hCA II). Records of Natural Products, 13(3), 225.
• Balcı, N., Çelik, H., Türkan, F., Çelebioğlu, N., Çelik, T., ve Bursal, E. (2023). Schiff Base Synthesis with a New Reliable Method and Investigation of Their Inhibition Effects on Glutathione S‐Transferase and Cholinesterase Enzymes. ChemistrySelect, 8(18), e202204566.
• Boy, S., Türkan, F., Beytur, M., Aras, A., Akyıldırım, O., Karaman, H. S., ve Yüksek, H. (2021). Synthesis, design, and assessment of novel morpholine-derived Mannich bases as multifunctional agents for the potential enzyme inhibitory properties including docking study. Bioorganic Chemistry, 107, 104524.
• Brimijoin, S., Chen, V. P., Pang, Y.-P., Geng, L., ve Gao, Y. (2016). Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis. Chemico-biological interactions, 259, 271-275.
• Buffat, M. G. (2004). Synthesis of piperidines. Tetrahedron, 60(8), 1701-1729.
• Cetin, A., Bursal, E., ve Türkan, F. (2021). 2-methylindole analogs as cholinesterases and glutathione S-transferase inhibitors: Synthesis, biological evaluation, molecular docking, and pharmacokinetic studies. Arabian Journal of Chemistry, 14(12), 103449.
• Cetin, A., Oguz, E., ve Türkan, F. (2022). In Silico and In Vitro Analysis of Acetylcholinesteraseand Glutathione S-Transferase Enzymes of Substituted Pyrazoles. Russian Journal of General Chemistry, 92(11), 2415-2428.
• Demir, Z., ve Türkan, F. (2022). Asetilkolinesteraz ve Bütirilkolinesteraz Enzimlerinin Alzheimer Hastalığı ile İlişkisi. Journal of the Institute of Science and Technology, 12(4), 2386-2395.
• Ellman, G. L., Courtney, K. D., Andres Jr, V., ve Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology, 7(2), 88-95.
• Esmer, Y. İ. (2022). Bazı yeni hidrazon bileşiklerinin sentezi, karakterizasyonu ve antioksidan aktivitelerinin belirlenmesi. Batman Üniversitesi Lisansüstü Eğitim Enstitüsü,
• Gok, M., Cicek, C., Sari, S., ve Bodur, E. (2023). Novel activity of human BChE: Lipid hydrolysis. Biochimie, 204, 127-135.
• Greig, N. (2001). Utsuki 1T, Yu QS, Zhu XX, Holloway HW, Perry TA, Lee B, Ingram DK, Lahiri DK: A new therapeutic target in Alzheimer’s disease treatment: Attention to butyrylcholinesterase. Curr Med Res Opin, 17, 159-165.
• Greig, N. H., Utsuki, T., Ingram, D. K., Wang, Y., Pepeu, G., Scali, C., . . . Giordano, T. (2005). Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent. Proceedings of the National Academy of Sciences, 102(47), 17213-17218.
• Habig, W. H., Pabst, M. J., ve Jakoby, W. B. (1974). Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. Journal of biological Chemistry, 249(22), 7130-7139.
• Huey, R., Morris, G. M., ve Forli, S. (2012). Using AutoDock 4 and AutoDock vina with AutoDockTools: a tutorial. The Scripps Research Institute Molecular Graphics Laboratory, 10550(92037), 1000.
• Kasé, Y., Kataoka, M., ve Miyata, T. (1967). In vitro production of piperidine from pipecolic acid in the presence of brain tissue. Life Sciences, 6(22), 2427-2431.
• Kaya, C. (2018). Bazı piperidin türevi bileşiklerin sentezi ve olası antidepresan etkilerinin incelenmesi. Anadolu University (Turkey),
• Łażewska, D., Kuder, K., Ligneau, X., Schwartz, J.-C., Schunack, W., Stark, H., ve Kieć-Kononowicz, K. (2008). Piperidine variations in search for non-imidazole histamine H3 receptor ligands. Bioorganic ve medicinal chemistry, 16(18), 8729-8736.
• Łażewska, D., Ligneau, X., Schwartz, J.-C., Schunack, W., Stark, H., ve Kieć-Kononowicz, K. (2006). Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 receptor antagonists. Bioorganic ve medicinal chemistry, 14(10), 3522-3529.
• Lockridge, O., ve Masson, P. (2000). Pesticides and susceptible populations: people with butyrylcholinesterase genetic variants may be at risk. Neurotoxicology, 21(1-2), 113-126.
• Mukherjee, P. K., Kumar, V., Mal, M., ve Houghton, P. J. (2007). Acetylcholinesterase inhibitors from plants. Phytomedicine, 14(4), 289-300.
• Neurath, G., Dünger, M., Pein, F., Ambrosius, D., ve Schreiber, O. (1977). Primary and secondary amines in the human environment. Food and Cosmetics Toxicology, 15(4), 275-282.
• Orhan, O. (2011). Glutatyon S-transferaz gen polimorfizmi ve gestasyonel diabetes mellitus ile ilişkisi. Bursa Uludag University (Turkey).
• Trott, O., ve Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry, 31(2), 455-461.
• Turan, N., Buldurun, K., Adiguzel, R., Aras, A., Turkan, F., ve Bursal, E. (2021). Investigation of spectroscopic, thermal, and biological properties of FeII, CoII, ZnII, and RuII complexes derived from azo dye ligand. Journal of Molecular Structure, 1244, 130989.
• Turkan, F., Cetin, A., Taslimi, P., Karaman, H. S., ve Gulçin, İ. (2019a). Synthesis, characterization, molecular docking and biological activities of novel pyrazoline derivatives. Archiv Der Pharmazie, 352(6), 1800359.
• Turkan, F., Cetin, A., Taslimi, P., Karaman, M., ve Gulçin, İ. (2019b). Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors. Bioorganic Chemistry, 86, 420-427.
• Türkan, F., ve Atalar, M. N. (2018). Glutatyon S-Transferaz Enzim Aktivitesi Üzerine Amoksilin ve Vankomisin Hidroklorid Hidratın Etkisi: Bir in vitro çalışma. Journal of the Institute of Science and Technology, 8(2), 141-148.
• Türkan, F., Calimli, M. H., Kanberoğlu, G. S., ve Karaman, M. (2021). Inhibition effects of isoproterenol, chlorpromazine, carbamazepine, tamoxifen drugs on glutathione S-transferase, cholinesterases enzymes and molecular docking studies. Journal of Biomolecular Structure and Dynamics, 39(9), 3277-3284.
• Türkan, F., ve Huyut, Z. (2018). Inhibition behaviour of some antibiotics on glutathione S-transferase and acetyl cholinesterase activities: in vitro and in vivo. Journal of Cellular Neuroscience ve Oxidative Stress, 10(2).
• Türkan, F., Huyut, Z., Taslimi, P., Huyut, M. T., ve Gülçin, İ. (2020). Investigation of the effects of cephalosporin antibiotics on glutathione S-transferase activity in different tissues of rats in vivo conditions in order to drug development research. Drug and chemical toxicology, 43(4), 423-428.
• Umar, A. M., ve Aisami, A. (2020). Acetylcholinesterase enzyme (AChE) as a biosensor and biomarker for pesticides: A mini review. Bulletin of Environmental Science and Sustainable Management (e-ISSN 2716-5353), 4(1), 7-12.
• Yuriev, E., ve Ramsland, P. A. (2013). Latest developments in molecular docking: 2010–2011 in review. Journal of Molecular Recognition, 26(5), 215-239.