Novel Trifluoromethyl Containing Azo-Imin compounds: Synthesis, Characterization, and Investigation of Antioxidant Properties Using In Vitro and In Silico methods

Öz

Abstract: In this study, two new molecules 4-((4-methoxyphenyl)diazenyl)-2-(((4-(trifluoromethyl)phenyl)imino)methyl)phenol (3a) and 2-(((4-methoxyphenyl)imino)methyl)-4-((4-(trifluoromethyl)phenyl)diazenyl)phenol (3b) were synthesized. The 1H-NMR, FTIR, UV-vis, and Mass analysis techniques were used to confirm the structures of the 3a and 3b. CUPRAC in vitro antioxidant activity method was also used to investigate the antioxidant properties of synthesized compounds. The compounds' ADME and toxicity parameters were also computed using SwissADME, Protox-II web servers respectively. In silico Molecular docking studies were conducted utilizing four different antioxidant proteins, such as PDB ID: 1N8Q for Lipoxygenase, 1OG5 for CYP2C9, 2CDU for NADPH oxidase, and 4JK4 for Bovine Serum Albumin, to investigate the potential antioxidant properties of the synthesized compounds 3a and 3b. ADME and toxicity (ADMEt) results showed that pharmacokinetic, physico-chemical, drug-similarity, and toxicity data were all appropriate for a potential bioactive agent. Molecular docking results have shown that all docking results were higher than standard (Trolox). The best docking score (-9.4 kcal/mol) was between 3b ligand and 2CDU protein. TEAC values of compounds were also higher than standard which was in harmony with molecular docking scores. From all obtained data It was concluded that the compound 3b has the potential antioxidant agent.

Anahtar Kelimeler

• Schiff Base
• CUPRAC Method
• Antioxidant
• Molecular Docking
• ADMEt

Triflorometil içeren Yeni Azo-İmin Bileşikleri: Sentezi, Karakterizasyonu, in siliko ve in vitro Yöntemlerle Antioksidan Özelliklerinin Araştırılması

Öz

Bu çalışmada iki yeni molekül 4-((4-metoksifenil)diazenil)-2-(((4-(triflorometil)fenil)imino)metil)fenol (3a) ve 2-(((4-metoksifenil)imino) metil)-4-((4-(triflorometil)fenil)diazenil)fenol (3b) sentezlendi. 3a ve 3b'nin yapılarını doğrulamak için 1H-NMR, FTIR, UV-vis ve Kütle analiz teknikleri kullanıldı. Sentezlenen bileşiklerin antioksidan özelliklerini araştırmak için CUPRAC in vitro antioksidan aktivite yöntemi de kullanıldı. Bileşiklerin ADME ve toksisite parametreleri de sırasıyla SwissADME, Protox-II web sunucuları kullanılarak hesaplandı. Sentezlenen bileşikler 3a ve 3b'nin potansiyel antioksidan özelliklerini araştırmak için PDB ID: Lipoksijenaz için 1N8Q, CYP2C9 için 1OG5, NADPH oksidaz için 2CDU ve Sığır Serum Albümini için 4JK4 gibi dört farklı antioksidan protein kullanılarak in siliko moleküler yerleştirme çalışmaları yapıldı. ADME ve toksisite (ADMEt) sonuçları, farmakokinetik, fiziko-kimyasal, ilaç benzerliği ve toksisite verilerinin tamamının potansiyel bir biyoaktif madde için uygun olduğunu gösterdi. Moleküler yerleştirme sonuçları, tüm yerleştirme sonuçlarının standarttan (Troloks) daha yüksek olduğunu göstermiştir. En iyi kenetlenme skoru (-9,4 kcal/mol), 3b ligandı ile 2CDU proteini arasındaydı. Bileşiklerin TEAC değerleri de standarttan daha yüksekti ve bu da moleküler yerleştirme skorlarıyla uyumluydu. Elde edilen tüm verilerden, bileşik 3b'nin potansiyel antioksidan özelliğe sahip olduğu sonucuna varılmıştır.

Anahtar Kelimeler

• Schiff Bazı
• CUPRAC Metod
• Antioksidan
• Moleküler Kenetlenme
• ADMEt

Kaynakça

1. [1] Sies, T. 2020. Oxidative Stress: Concept and Some Practical Aspects. Antioxidants, 9, 852.
2. [2] Preiser, J. 2012. Oxidative Stress. Journal of Parenteral and Enteral Nutrition, 36, 147–154.
3. [3] Matés, J. M., Segura, J. A., Alonso, F. J., Márquez, J. 2012. Oxidative stress in apoptosis and cancer: an update. Archives of Toxicology, 86, 1649–1665.
4. [4] Houldsworth, A. 2023. Role of oxidative stress in neurodegenerative disorders: a review of reactive oxygen species and prevention by antioxidants. Brain Communications, 6.
5. [5] Zhang, Y., Seeram, N. P., Lee, R., Feng, L., Heber, D. 2008. Isolation and Identification of Strawberry Phenolics with Antioxidant and Human Cancer Cell Antiproliferative Properties, Journal of Agricultural and Food Chemistry, 56, 670–675.
6. [6] Kaur, S., Das, M. 2011. Functional foods: An overview. Food Science and Biotechnology, 20, 861–875.
7. [7] Alarcón-Flores, M. I., Romero-González, R., Vidal, J. L. M., Frenich, A. G. 2013. Multiclass determination of phytochemicals in vegetables and fruits by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. Food Chemistry, 141, 1120–1129.
8. [8] Pallauf, K., Bendall, J. K., Scheiermann, C., Watschinger, K., Hoffmann, J., Roeder, T., Rimbach, G. 2013. Vitamin C and lifespan in model organisms. Food and Chemical Toxicology, 58, 255–263.

9. [9] Abula, A., Xu, Z., Zhu, Z., Peng, C., Chen, Z., Zhu, W., Aisa, H. A. 2020. Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations. Journal of Chemical Information and Modeling, 60, 6242–6250.
10. [10] Sap, J. B. I., Straathof, N. J. W., Knauber, T., Meyer, C.F., Médebielle, M., Buglioni, L., Genicot, C., Trabanco, A. A., Noël, T., am Ende, C. W., Gouverneur, V. 2020. Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery. Journal of the American Chemical Society, 142, 9181–9187.
11. [11] Swallow, S. 2015. Fluorine in Medicinal Chemistry. pp. 65–133. Lawton, G., Witty, D. R., ed. Progress in Medicinal Chemistry, Elsevier B.V.
12. [12] Dilek, Ö., Dede, B., Karabacak Atay, Ç., Tilki, T. 2024. Promising agent for the efficient extraction of Co(II) ions from aqueous medium and its metal complexes: Synthesis, theoretical calculations and solvent extraction. Polyhedron, 250, 116843.
13. [13] Wei, L., Tan, W., Wang, G., Li, Q., Dong, F., Guo, Z. 2019. The antioxidant and antifungal activity of chitosan derivatives bearing Schiff bases and quaternary ammonium salts. Carbohydrate Polymers, 226, 115256.
14. [14] Haj Mohammad Ebrahim Tehrani, K., Hashemi, M., Hassan, M., Kobarfard, F., Mohebbi, S. 2016. Synthesis and antibacterial activity of Schiff bases of 5-substituted isatins. Chinese Chemical Letters, 27, 221–225.
15. [15] Bekhit, A. A., Saudi, M. N., Hassan, A. M. M., Fahmy, S. M., Ibrahim, T. M., Ghareeb, D., El-Seidy, A. M., Nasralla, S. N., Bekhit, A.E.-D.A. 2019. Synthesis, in silico experiments and biological evaluation of 1,3,4-trisubstituted pyrazole derivatives as antimalarial agents. European Journal of Medicinal Chemistry, 163, 353–366.
16. [16] Iacopetta, D., Ceramella, J., Catalano, A., Saturnino, C., Bonomo, M. G., Franchini, C., Sinicropi, M. S. 2021. Schiff Bases: Interesting Scaffolds with Promising Antitumoral Properties. Applied Sciences, 11, 1877.
17. [17] Dilek, Ö. 2024. Imidazole Based Novel Schiff Base: Synthesis, Characterization, Quantum Chemical Calculations, In Silico Investigation of ADMEt Properties and Molecular Docking Simulations against VEGFR2 Protein. Bitlis Eren Üniversitesi Fen Bilimleri Dergisi, 13, 62–78.
18. [18] Kitouni, S., Chafai, N., Chafaa, S., Houas, N., Ghedjati, S., Djenane, M. 2023. Antioxidant activity of new synthesized imine and its corresponding α-aminophosphonic acid: Experimental and theoretical evaluation. Journal of Molecular Structure, 1281, 135083.
19. [19] Huang, D. D., Pozhidaev, E. P., Chigrinov, V. G., Cheung, H. L., Ho, Y. L., Kwok, H. S. 2004. Photo-aligned ferroelectric liquid crystal displays based on azo-dye layers. Displays, 25, 21–29.
20. [20] Borbone, F., Carella, A., Ricciotti, L., Tuzi, A., Roviello, A., Barsella, A. 2011. High nonlinear optical response in 4-chlorothiazole-based azo dyes. Dyes and Pigments, 88, 290–295.
21. [21] El-Sonbati, A. Z., Diab, M. A., El-Bindary, A. A., Shoair, A. F., Hussein, M. A., El-Boz, R. A. 2017. Spectroscopic, thermal, catalytic and biological studies of Cu(II) azo dye complexes. Journal of Molecular Structure, 1141, 186–203.
22. [22] Mitra, A., Mawson, A. 2017. Neglected Tropical Diseases: Epidemiology and Global Burden. Tropical Medicine and Infectious Disease, 2, 36.
23. [23] Karabacak Atay, Ç., Dilek, Ö., Tilki, T., Dede, B. 2023. A novel imidazole-based azo molecule: synthesis, characterization, quantum chemical calculations, molecular docking, molecular dynamics simulations and ADMET properties. Journal of Molecular Modeling, 29, 226.
24. [24] Saeed, A. M., AlNeyadi, S. S., Abdou, I. M. 2020. Anticancer activity of novel Schiff bases and azo dyes derived from 3-amino-4-hydroxy-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione. Heterocyclic Communications, 26, 192–205.
25. [25] Chhetri, A., Chettri, S., Rai, P., Mishra, D. K., Sinha, B., Brahman, D. 2021. Synthesis, characterization and computational study on potential inhibitory action of novel azo imidazole derivatives against COVID-19 main protease (Mpro: 6LU7). Journal of Molecular Structure, 1225.
26. [26] Kasare, M. S., Dhavan, P. P., Shaikh, A. H. I., Jadhav, B. L., Pawar, S.D. 2022. Novel Schiff base scaffolds derived from 4‐aminoantipyrine and 2‐hydroxy‐3‐methoxy‐5‐(phenyldiazenyl) benzaldehyde: Synthesis, antibacterial, antioxidant and anti‐inflammatory. Journal of Molecular Recognition, 35.
27. [27] Maliyappa, M. R., Keshavayya, J., Sudhanva, M.S., Pushpavathi, I., Kumar, V. 2022. Heterocyclic azo dyes derived from 2-(6-chloro-1,3-benzothiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one having benzothiazole skeleton: Synthesis, structural, computational and biological studies. Journal of Molecular Structure, 1247, 131321.
28. [28] Niu, Y., Lin, P. 2023. Advances of computer-aided drug design (CADD) in the development of anti-Azheimer’s-disease drugs. Drug Discovery Today, 28, 103665.
29. [29] Khanmohammadi, H., Khodam, F. 2013. Solvatochromic and electrochemical properties of new thermally stable azo–azomethine dyes with N2S2O2 donor set of atoms. Journal of Molecular Liquids, 177, 198–203.
30. [30] Sun, Y. F., Xu, S. H., Wu, R. T., Wang, Z. Y., Zheng, Z. B., Li, J. K., Cui, Y. P. 2010. The synthesis, structure and photoluminescence of coumarin-based chromophores. Dyes and Pigments, 87(2), 109-118.
31. [31] Apak, R., Güçlü, K., Özyürek, M., Çelik, S.E. 2008. Mechanism of antioxidant capacity assays and the CUPRAC (cupric ion reducing antioxidant capacity) assay. Microchimica Acta, 160, 413–419.
32. [32] Daina, A., Michielin, O., Zoete, V. 2017. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 42717.
33. [33] Banerjee, P., Eckert, A. O., Schrey, A. K., Preissner, R. 2018. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Research, 46, 257–263.
34. [34] Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., Hutchison, G. R. 2012. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics, 4, 17.
35. [35] Trott, O., 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, 455–461.
36. [36] Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., Ferrin, T. E. 2004. UCSF Chimera-A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25, 1605–1612.
37. [37] BIOVIA (2021). Discovery Studio Visualizer, version 21.1.0.20298. Dassault Systèmes, San Diego, CA.
38. [38] Berman, H. M. 2000. The Protein Data Bank. Nucleic Acids Research, 28, 235–242.
39. [39] Kandsi, F., Elbouzidi, A., Lafdil, F. Z., Meskali, N., Azghar, A., Addi, M., Hano, C., Maleb, A., Gseyra, N. 2022. Antibacterial and Antioxidant Activity of Dysphania ambrosioides (L.) Mosyakin and Clemants Essential Oils: Experimental and Computational Approaches. Antibiotics, 11, 482.
40. [40] Bouzammit, R., Lakkab, I., El fadili, M., Kanzouai, Y., Chalkha, M., Nakkabi, A., El Bali, B., Obbade, S., Jouffret, L., Lachkar, M., Al Houari, G. 2024. Synthesis, crystal structure, antioxidant activity and molecular docking studies of 2-(1-(3-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)ethyl)malononitrile. Journal of Molecular Structure, 1312, 138582.
41. [41] Ulutürk, M., Karabacak Atay, Ç., Dede, B., Tilki, T. 2023. Potentially Bioactive Novel Isophthalic Acid Based Azo Molecules: Synthesis, Characterization, Quantum Chemical Calculations, ADMET Properties, Molecular Docking and Molecular Dynamics Simulations. Polycyclic Aromatic Compounds, 1–22.
42. [42] Veber, D. F., Johnson, S. R., Cheng, H. Y., Smith, B. R., Ward, K. W., Kopple, K. D. 2002. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. Journal of Medicinal Chemistry, 45, 2615–2623.
43. [43] Lakhera, S., Devlal, K., Ghosh, A., Rana, M. 2021. In silico investigation of phytoconstituents of medicinal herb ‘Piper Longum’ against SARS-CoV-2 by molecular docking and molecular dynamics analysis. Results in Chemistry, 3, 100199.