Novel 1,2,3-Triazole Compounds Containing Different Amine Groups: Synthesis, Characterization and in Silico Studies on Xanthine Oxidase

Year 2022, , 508 - 516, 30.06.2022

Ayşe Tan

https://doi.org/10.35414/akufemubid.1105960

Abstract

In this study, novel 1,2,3-triazole derivatives containing different amine subunits 16(a-c) and 17(a-c) were synthesized and characterized by FT-IR, HRMS, 1H, and 13C NMR analyses. The interactions with xanthine oxidase (XO) enzyme of these compounds were investigated with molecular docking studies. The obtained results were compared with molecular docking studies of allopurinol and febuxostat, which are the XO inhibitors. All target compounds demonstrated better binding energies than allopurinol in the interaction with the XO. On the other hand, 16a and 17a exhibited better binding affinities than febuxostat. The best binding energy values of the target compounds, allopurinol, and febuxostat vary between -6.1 and 9.84 kcal/mol. In this case, the target compounds may show better activity than allopurinol against the XO in vitro enzyme-inhibition studies. Additionally, compounds 16a and 17a may show better activities than febuxostat, as well. Finally, in silico ADME and toxicity studies for all target compounds were performed. The ADME results suggested suitable drug-likeness values for the compounds. Regarding toxicity, the compounds are predicted to be safe in terms of mutagenicity and tumorigenicity.

Keywords

Xanthine oxidase, 1,2,3-triazole, Allopurinol, Febuxostat, ADMET, Molecular docking

Supporting Institution

Muş Alparslan Üniversitesi

Project Number

BAP-21-TBMY-4901-01

Thanks

The author thanks to Mus Alparslan University

Farklı Amin Grupları İçeren Yeni 1,2,3-Triazol bileşikleri: Sentez, Karakterizasyon ve Ksantin Oksidaz üzerine in Siliko Çalışmalar

Abstract

Bu çalışmada, farklı amin alt birimleri içeren yeni 1,2,3-triazol türevleri 16(a-c) ve 17(a-c) sentezlendi ve FT-IR, HRMS, 1H, ve 13C NMR analizleri ile yapıları karakterize edildi. Bu bileşiklerin ksantin oksidaz (XO) enzimi ile etkileşimleri moleküler yerleştirme çalışmaları ile incelendi. Elde edilen sonuçlar, XO inhibitörleri olarak bilinen allopurinol ve febuksostat’in moleküler yerleştirme çalışmaları ile karşılaştırıldı. Hedef bileşikler, XO ile etkileşimlerde allopurinolden daha iyi bağlanma enerjileri gösterdi. Diğer taraftan, 16a ve 17a bileşikleri, febuksostat’tan daha iyi bağlanma affiniteleri sergiledi. Hedef bileşikleri, allopurinol ve febuksostatın en iyi bağlanma enerjisi değerleri -6.1 ile 9.84 kcal/mol arasında değişmektedir. Bu durumda, hedef bileşiklerinin in vitro enzim inhibisyon çalışmalarında XO'ya karşı allopurinolden daha iyi aktivite göstermesi olasıdır. Ayrıca, 16a ve 17a bileşikleri de febuksostattan daha iyi aktivite gösterebilir. Son olarak, tüm hedef bileşikler için in siliko ADME ve toksisite çalışmaları yapılmıştır. ADME sonuçları, bileşikler için kabul edilebilir ilaç benzerlik değerleri önerdi. Toksisite ile ilgili olarak, tüm bileşiklerin mutajenite ve tümörijenite açısından güvenli olduğu tahmin edilmektedir.

Keywords

Ksantin oksidaz, 1,2,3-triazol, Allopurinol, Febuksostat, ADMET, Moleküler yerleştirme

Project Number

BAP-21-TBMY-4901-01

References

• Aouad, M.R., 2017. Click Synthesis and antimicrobial screening of novel isatin-1, 2, 3-triazoles with piperidine, morpholine, or piperazine moieties. Organic Preparations and Procedures International, 49(3), 216-227.
• Biovia, D. S. (2021). Discovery Studio, version 21.1. 0. San Diego: Dassault Systèmes.
• Bunders, C., Cavanagh, J., and Melander, C., 2011. Flustramine inspired synthesis and biological evaluation of pyrroloindoline triazole amides as novel inhibitors of bacterial biofilms. Organic & biomolecular chemistry, 9(15), 5476-5481.
• Deshmukh, T.R., Khare, S.P., Krishna, V.S., Sriram, D., Sangshetti, J.N., Bhusnure, O., Shingate, B. B., 2019. Design and Synthesis of New Aryloxy‐linked Dimeric 1, 2, 3‐Triazoles via Click Chemistry Approach: Biological Evaluation and Molecular Docking Study. Journal of Heterocyclic Chemistry, 56(8), 2144-2162.
• Dommerholt, J., Van Rooijen, O., Borrmann, A., Guerra, C.F., Bickelhaupt, F.M., and Van Delft, F.L., 2014. Highly accelerated inverse electron-demand cycloaddition of electron-deficient azides with aliphatic cyclooctynes. Nature Communications, 5(1), 1-7.
• Frampton, J.E., 2015. Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout. Drugs, 75(4), 427-438.
• Ganesh, V., Sudhir, V.S., Kundu, T., and Chandrasekaran, S., 2011. 10 years of click chemistry: synthesis and applications of ferrocene‐derived triazoles. Chemistry–An Asian Journal, 6(10), 2670-2694.
• Garudachari, B., Isloor, A.M., Satyanarayana, M., Fun, H.K., and Hegde, G., 2014. Click chemistry approach: Regioselective one-pot synthesis of some new 8-trifluoromethylquinoline based 1, 2, 3-triazoles as potent antimicrobial agents. European journal of medicinal chemistry, 74, 324-332.
• Hans, R.H., Guantai, E.M., Lategan, C., Smith, P.J., Wan, B., Franzblau, S. G.,Chibale, K., 2010. Synthesis, antimalarial and antitubercular activity of acetylenic chalcones. Bioorganic & medicinal chemistry letters, 20(3), 942-944 (and therein).
• Himo, F., Lovell, T., Hilgraf, R., Rostovtsev, V.V., Noodleman, L., Sharpless, K.B., & Fokin, V.V., 2005. Copper (I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. Journal of the American chemical society, 127(1), 210-216.
• Hou, D.R., Hung, M.S., Liao, C.C., and Lin, C.C., 2012. 1, 2, 3-Triazole derivatives as new cannabinoid-1 receptor antagonists. In: Google Patents.
• Lee, D., Kim, D., Lee, S., Kim, T., Kim, J., Kim, S., Song, K.S., 2015. Efficient syntheses of 1, 2, 3-Triazoloamide derivatives using solid-and solution-phase synthetic approaches. Molecules, 20(11), 19984-20013.
• Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., and Olson, A.J., 2009. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry, 30(16), 2785-2791.
• Pillinger, M.H., and Mandell, B. F. (2020). Therapeutic approaches in the treatment of gout. In Seminars in Arthritis and Rheumatism, 50(3), 24-S30. WB Saunders.
• Pokhodylo, N., Savka, R., and Obushak, M., 2020. Synthesis of (1 H-1, 2, 3-Triazol-1-yl) acetic Acid Derivatives. Russian Journal of Organic Chemistry, 56(8), 1421-1431.
• Tan, A., 2020. Novel 1, 2, 3-triazole compounds: Synthesis, In vitro xanthine oxidase inhibitory activity, and molecular docking studies. Journal of Molecular Structure, 1211, 128060.
• Tan, A. 2021. Ksantin Oksidaz İnhibitörü Yeni 1, 2, 3-triazol Türevlerinin Sentezi, Karakterizasyonu ve Moleküler Doking Çalışmaları. Bitlis Eren Üniversitesi Fen Bilimleri Dergisi, 9(2), 644-654.
• Tan, A. 2022. Synthesis, spectroscopic characterization of novel phthalimides derivatives bearing a 1, 2, 3-triazole unit and examination as potential SARS-CoV-2 inhibitors via in silico studies. Journal of Molecular Structure, 1261, 132915.
• Whiting, M., Muldoon, J., Lin, Y.C., Silverman, S.M., Lindstrom, W., Olson, A.J., Elder, J.H., 2006. Inhibitors of HIV‐1 protease by using in situ click chemistry. Angewandte Chemie, 118(9), 1463-1467.
• Internet Resources 1. http://www.swissadme.ch/, (01.04.2022) 2. https://www.rcsb.org/,(01.04.2022) 3. https://www.organicchemistry.org/prog/peo/, (01.04.2022)