The Synthesis, Characterization and Molecular Docking Studies of Novel 1,2,3-Triazole Derivatives as Xanthine Oxidase Inhibitor

Year 2020, Volume: 9 Issue: 2, 644 - 654, 15.06.2020

Ayşe Tan

https://doi.org/10.17798/bitlisfen.644565

Cited By: 7

Abstract

In this study, the synthesis, characterization of novel 1,2,3-triazole compounds (4 and 5), investigation of their in vitro inhibition effects on xanthine oxidase and molecular docking studies were carried out. For this purpose, firstly; the target products (4 and 5) were synthesized by various chemical transformations starting from butadiene sulfone. All of the synthesized compounds were characterized by spectroscopic methods. In the second step; in vitro inhibition effects of compounds 4 and 5 on xanthine oxidase were investigated. According to the enzyme inhibition results, It was determined that compounds 4 (IC50 = 0.609 µM) and 5 (IC50 = 0.901 µM) showed stronger inhibition effect than allopurinol (IC50 = 1.143 µM), which is used as a drug for inhibition of xanthine oxidase. Finally, the binding modes of compounds 4 and 5 in the active part of xanthine oxidase (PDB ID:3NVY) were explained by molecular docking studies.

Keywords

1,2,3-triazole , Xanthine oxidase , 1,3-dipolar cycloaddition , Molecular docking

Ksantin Oksidaz İnhibitörü Yeni 1,2,3-triazol Türevlerinin Sentezi, Karakterizasyonu ve Moleküler Doking Çalışmaları

Abstract

Bu çalışmada, yeni 1,2,3-triazol bileşiklerinin (4
ve 5) sentezi, karakterizasyonu, ksantin oksidaz enzimi üzerine in vitro inhibisyon
etkilerinin incelenmesi ve moleküler doking çalışmaları
gerçekleştirildi. Bu amaçla öncelikle; hedef ürünler (4 ve 5),
bütadien sülfondan çıkılarak çeşitli kimyasal transformasyonlarla sentezlendi.
Sentezlenen bütün bileşiklerin yapıları spektroskopik yöntemlerle aydınlatıldı. İkinci aşamada; 4
ve 5 bileşiklerinin ksantin
oksidaz enzimi üzerine in vitro inhibisyon etkileri incelendi. Enzim
inhibisyon sonuçlarına göre; 4 (IC₅₀ =
0.609 µM) ve 5 (IC₅₀ = 0.901 µM) bileşiklerinin, ksantin
oksidaz enzim inhibisyonu için
ilaç olarak kullanılan Allopurinol’den (IC₅₀ = 1.143 µM) daha
güçlü inhibisyon etki gösterdiği tespit edildi. Son olarak; 4 ve 5
bileşiklerinin, ksantin oksidaz eziminin (PDB ID:3NVY) aktif kısmına bağlanma modları, moleküler doking çalışmaları
ile açıklandı.

Keywords

triazol , moleküler doking , dipolar sikloadisyon

Thanks

Çalışmalarımda desteğini esirgemeyen sayın Yunus Kara’ya, sayın Samir Abbas Ali Noma’ya ve Sayın Burhan Ateş’e teşekkür ederim.

References

• [1] Mehta S.K., Nayeem N. 2014. Natural xanthine oxidase inhibitors for management of gout: a review. Research and reviews: journal of medical and health sciences, 3: 4-13.
• [2] Borges F., Fernandes E., Roleira F. 2002. Progress towards the discovery of xanthine oxidase inhibitors. Current medicinal chemistry, 9: 195-217.
• [3] Kıbrız İ.E., Saçmacı M., Yıldırım İ., Abbas Ali Noma S., Taşkın T.T., Ateş B. 2018. Xanthine oxidase inhibitory activity of new pyrrole carboxamide derivatives: In vitro and in silico studies. Archiv der pharmazie, 351 (10): 1800165. [4] Pacher P., Nivorozhkin A., Szabo C. 2006. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacological reviews, 58: 87-114.
• [5] Baldwin J., Kasinger P., Novello F., Sprague J., Duggan D. 1975. 4-trifluoromethylimidazoles and 5-(4-pyridyl)-1, 2, 4-triazoles, new classes of xanthine oxidase inhibitors. Journal of medicinal chemistry, 18: 895-900.
• [6] Wang S., Yan J., Wang J., Chen J., Zhang T., Zhao Y., Xue M. 2010. Synthesis of some 5-phenylisoxazole-3-carboxylic acid derivatives as potent xanthine oxidase inhibitors. European journal of medicinal chemistry, 45: 2663-2670.
• [7] Ishibuchi S., Morimoto H., Oe T., Ikebe T., Inoue H., Fukunari A., Kamezawa M., Yamada I., Naka Y. 2001. Synthesis and structure–activity relationships of 1-phenylpyrazoles as xanthine oxidase inhibitors. Bioorganic & medicinal chemistry letters, 11: 879-882.
• [8] Shukla S., Kumar D., Ojha R., Gupta M.K., Nepali K., Bedi P.M. 2014. 4, 6‐diaryl/heteroarylpyrimidin‐2 (1h)‐ones as a new class of xanthine oxidase inhibitors. Archiv der pharmazie, 347: 486-495.
• [9] Song J.U., Choi S.P., Kim T.H., Jung C.-K., Lee J.-Y., Jung S.-H., Kim G.T. 2015. Design and synthesis of novel 2-(indol-5-yl) thiazole derivatives as xanthine oxidase inhibitors. Bioorganic & medicinal chemistry letters, 25: 1254-1258.
• [10] Phatak P.S., Bakale R.D., Dhumal S.T., Dahiwade L.K., Choudhari P.B., Krishna V.S., Sriram D., Haval K.P. 2019. Synthesis, antitubercular evaluation and molecular docking studies of phthalimide bearing 1,2,3-triazoles. Synthetic communications, 49: 2017-2028.
• [11] Rajasekar S., Anbarasan P. 2019. A general proline catalyzed synthesis of 4, 5‐disubstituted n‐sulfonyl‐1, 2, 3‐triazoles from 1, 3‐dicarbonyl compounds and sulfonyl azide. Chemistry-an asian journal, https://doi.org/10.1002/asia.201901015.
• [12] Kushwaha K., Kaushik N., Jain S.C. 2014. Design and synthesis of novel 2H-chromen-2-one derivatives bearing 1, 2, 3-triazole moiety as lead antimicrobials. Bioorganic & medicinal chemistry letters, 24: 1795-1801.
• [13] Wang G., Peng Z., Wang J., Li J., Li X.2016. Synthesis and biological evaluation of novel 2, 4, 5-triarylimidazole–1, 2, 3-triazole derivatives via click chemistry as α-glucosidase inhibitors. Bioorganic & medicinal chemistry letters, 26: 5719-5723.
• [14] Li L.-T., Zhou L.-F., Li Y.-J., Huang J., Liu R.-H., Wang B., Wang P. 2012. Facile synthesis of 1, 2, 3-triazole analogs of SGLT2 inhibitors by ‘click chemistry. Bioorganic & medicinal chemistry letters, 22: 642-644.
• [15] Röhrig U.F., Majjigapu S.R., Grosdidier A.I., Bron S., Stroobant V., Pilotte L., Colau D., Vogel P., Van den Eynde B.J., Zoete V. 2012. Rational design of 4-aryl-1, 2, 3-triazoles for indoleamine 2, 3-dioxygenase 1 inhibition. Journal of medicinal chemistry, 55: 5270-5290.
• [16] González-Olvera R., Espinoza-Vázquez A., Negrón-Silva G., Palomar-Pardavé M., Romero-Romo M., Santillan R. 2013. Multicomponent click synthesis of new 1, 2, 3-triazole derivatives of pyrimidine nucleobases: Promising acidic corrosion inhibitors for steel. Molecules, 18: 15064-15079.
• [17] DiFrancesco D., Pinhas A.R. 1986. The nickel-promoted 1, 3-migration of an sp2 center; ring expansion of a vinylcyclobutene. The Journal of organic chemistry, 51: 2098-2102.
• [18] Kuhn T., Tamm C., Riesen A., Zehnder M. 1989. Stereoselective hydrolysis of the dimethyl 4, 5-epoxy-1, 2-cis-cyclohexanedicarboxylates with pig liver esterase (PLE). Tetrahedron letters, 30: 693-696.
• [19] Hudlicky T., Fan R., Reed J.W., Gadamasetti K.G. 1992. Divinylcyclopropane-cycloheptadiene rearrangement. Org. React., (Hoboken, NJ, U. S.) 41: No pp. given.
• [20] Voskresenskii V.A., Shakirzyanova S.S., Byl'ev V.A. 1962. Some regularities in the plasticizing of poly(vinyl chloride) with oxides of tetrahydrophthalates. Izv. vyssh. uchebn. zaved., khim. khim. tekhnol., 5: 322-325.
• [21] Acquaah-Harrison, G. 2010. Antibacterial agents: 1, 4-disubstituted 1, 2, 3-triazole analogs of the oxazolidinone. Doctor of philosophy, The faculty of the college of arts and sciences of Ohio University.
• [22] 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: 210-216.
• [23] Worrell B.T., Malik J.A., Fokin V.V. 2013. Direct evidence of a dinuclear copper intermediate in Cu (I)-catalyzed azide-alkyne cycloadditions. Science, 340: 457-460.
• [24] Tan A. 2020. Novel 1, 2, 3-triazole compounds: Synthesis, In vitro xanthine oxidase inhibitory activity, and molecular docking studies. J. Mol. Struct., 128060.
• [25] Sweeney A.P., Wyllie S.G., Shalliker R.A., Markham J. 2001. Xanthine oxidase inhibitory activity of selected Australian native plants. Journal of ethnopharmacology, 75 (2-3): 273-277.
• [26] Nile S.H., Kumar B., Park S.W. 2013. In vitro evaluation of selected benzimidazole derivatives as an antioxidant and xanthine oxidase inhibitors. Chemical biology & drug design., 82: 290-295.
• [27] Hassan M., Ashraf Z., Abbas Q., Raza H., Seo S.-Y. 2018. Exploration of novel human tyrosinase inhibitors by molecular modeling, docking and simulation studies. Interdisciplinary sciences: computational life sciences, 10: 68-80.
• [28] Hassan M., Abbas Q., Ashraf Z.A. Moustafa A., Seo S.-Y. 2017. Pharmacoinformatics exploration of polyphenol oxidases leading to novel inhibitors by virtual screening and molecular dynamic simulation study. Computational biology and chemistry, 68: 131-142.
• [29] Langham J. 2014. Ranking small molecules by how much they preferentially inhibit the growth of cancer cell lines with either BRAF or KRAS oncogene mutations. Peer J PrePrints, 2: e532v1.
• [30] Maroli N., Kolandaivel P., 2019. Comparative study of stability and transport of molecules through cyclic peptide nanotube and aquaporin: A molecular dynamics simulation approach. Journal of Biomolecular Structure and Dynamics, 1-14.
• [31] Berman H., Westbrook J., Feng Z., Gilliland G., Bhat T., Weissig H., Shindyalov I., Bourne P. 2000. The protein data Bank nucleic acids research, 28: 235-242. URL: www. rcsb. org Citation.
• [32] 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 (1): 17.
• [33] 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 (13): 1605-1612.
• [34] 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.
• [35] Biovia D.S. 2017. Discovery studio visualizer, Release 2017, San Diego: Dassault Systèmes, 2016. to be found under http://accelrys. com/products/collaborative-science/biovia-discovery-studio/visualization-download. php (accessed: 12.12.2017).