English version Ukrainian version
Last issue Archive Editorial board Instructions to authors Contact us

This site supported by

Ukr. Bioorg. Acta 2021, Vol. 16, N2, 12-22.

Nitro-substituted aurones as xanthine oxidase inhibitors

Oleksandr L. Kobzar1, Iryna M. Mischenko1, Alona V. Tatarchuk1, Vasyl S. Vdovin2, Sergiy S. Lukashov2, Sergiy M. Yarmoluk2 and Andriy I. Vovk1*

1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine,
1 Murmanska St., Kyiv, 02094, Ukraine

tel.: +380-44-558-5388; e-mail: vovk@bpci.kiev.ua
2 Institute of Molecular Biology and Genetics of the National Academy of Sciences of Ukraine, 150 Zabolotnogo St., 03143 Kyiv, Ukraine

Aurone derivatives possessing a wide range of biological activities are of high interest in medicinal chemistry. Carboxylated aurones were found previously to inhibit xanthine oxidase, which is a potential target for treatment of hyperuricemia and gout. In this paper, a series of B-ring nitro-substituted aurone derivatives were studied in vitro as inhibitors of this enzyme. The introduction of hydroxyl group into the B-ring of nitro-functionalized aurones resulted in significant increase of their inhibitory potency. At the same time, aurones chlorinated at ring A and containing nitro and hydroxyl groups at ring B showed only slightly increased inhibition effect. The kinetic studies and molecular docking calculations were carried out to explain the inhibition mechanism of xanthine oxidase by the nitro-substituted aurone derivatives.

aurone; xanthine oxidase; inhibition; kinetics; molecular docking.

Full text: (PDF, in English)


    1. Brondino, C. D.; Romao, M. J.; Moura, I.; Moura, J. J. G. Molybdenum and tungsten enzymes: the xanthine oxidase family. Curr. Opin. Chem. Biol. 2006, 10, 109-114.
    2.  Ribeiro, P. M.; Fernandes, H. S.; Maia, L. B.; Sousa, S. F.; Moura, J. J.; Cerqueira, N. M. The complete catalytic mechanism of xanthine oxidase: a computational study. Inorg. Chem. Front. 2021, 8, 405-416.
    3. Saito, H.; Tanaka, K.; Iwasaki, T.; Oda, A.; Watanabe, S.; Kanno, M.; Kimura, H.; Shimabukuro, M.; Asahi, K.; Watanabe, T.; Kazama, J. J. Xanthine oxidase inhibitors are associated with reduced risk of cardiovascular disease. Sci. Rep. 2021, 11, 1380.
    4. Battelli, M. G.; Polito, L.; Bortolotti, M.; Bolognesi, A. Xanthine oxidoreductase in cancer: more than a differentiation marker. Cancer Med. 2016, 5, 546-557.
    5. Pacher, P.; Nivorozhkin, A., Szabo, C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol. Rev. 2006, 58, 87-114.
    6. Jordan, A.; Gresser, U. Side effects and interactions of the xanthine oxidase inhibitor febuxostat. Pharmaceuticals (Basel). 2018, 11, 51.
    7. Luna, G.; Dolzhenko, A. V.; Mancera, R. L. Inhibitors of xanthine oxidase: scaffold diversity and structure-based drug design. ChemMedChem. 2019, 14, 714-743.
    8. Singh, J. V.; Bedi, P. M. S.; Singh, H.; Sharma, S. Xanthine oxidase inhibitors: patent landscape and clinical development (2015–2020). Expert Opin. Ther. Pat. 2020, 30, 769-780.
    9. Zhang, T.; Lv, Y.; Lei, Y.; Liu, D.; Feng, Y.; Zhao, J.; Chen, S.; Meng, F.; Wang, S. Design, synthesis and biological evaluation of 1-hydroxy-2-phenyl-4-pyridyl-1H-imidazole derivatives as xanthine oxidase inhibitors. Eur. J. Med. Chem. 2018, 146, 668-677.
    10. Wang, S.; Yan, J.; Wang, J.; Chen, J.; Zhang, T.; Zhao, Y.; Xue, M. Synthesis of some 5-phenylisoxazole-3-carboxylic acid derivatives as potent xanthine oxidase inhibitors. Eur. J. Med. Chem. 2010, 45, 2663-2670.
    11. Xu, X.; Deng, L.; Nie, L.; Chen, Y.; Liu, Y.; Xie, R.; Li, Z. Discovery of 2-phenylthiazole-4-carboxylic acid, a novel and potent scaffold as xanthine oxidase inhibitors. Bioorg. Med. Chem. Lett. 2019, 29, 525-528.
    12. Li, J.; Wu, F.; Liu, X.; Zou, Y.; Chen, H.; Li, Z.; Zhang, L. Synthesis and bioevaluation of 1-phenyl-pyrazole-4-carboxylic acid derivatives as potent xanthine oxidoreductase inhibitors. Eur. J. Med. Chem. 2017, 140, 20-30.
    13. Zhang, T.-J.; Wu, Q.-X.; Li, S.-Y.; Wang, L.; Sun, Q.; Zhang, Y.; Meng, F.-H.; Gao, H. Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as xanthine oxidase inhibitors. Bioorg. Med. Chem. Lett. 2017, 27, 3812-3816.
    14. Hayashi, T.; Sawa, K.; Kawasaki, M.; Arisawa, M.; Shimizu, M.; Morita, N. Inhibition of cow's milk xanthine oxidase by flavonoids. J. Nat. Prod. 1988, 51, 345-348.
    15. Santi, M. D.; Zunini, M. P.; Vera, B.; Bouzidi, C.; Dumontet, V.; Abin-Carriquiry, A.; Grougnet, R.; Ortega, M. G. Xanthine oxidase inhibitory activity of natural and hemisynthetic flavonoids from Gardenia oudiepe (Rubiaceae) in vitro and molecular docking studies. Eur. J. Med. Chem. 2018, 143, 577-582.
    16. Hofmann, E.; Webster, J.; Do, T.; Kline, R.; Snider, L.; Hauser, Q.; Higginbottom, G.; Campbell, A.; Ma, L.; Paula, S. Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers. Bioorg. Med. Chem. 2016, 24, 578-587.
    17. Singh, J. V.; Mal, G.; Kaur, G.; Gupta, M. K.; Singh, A.; Nepali, K.; Singh, H.; Sharma, S.; Bedi, P. M. S. Benzoflavone derivatives as potent antihyperuricemic agents. Medchemcomm. 2019, 10, 128-147.
    18. Costantino, L.; Rastelli, G.; Albasini, A. Natural polyhydroxylated compounds as inhibitors of xanthine oxidase. Pharmazie. 1996, 51, 994-995.
    19. Muzychka, O. V.; Kobzar, O. L.; Popova, A. V.; Frasinyuk, M. S.; Vovk, A. I. Carboxylated aurone derivatives as potent inhibitors of xanthine oxidase. Bioorg. Med. Chem. 2017, 25, 3606-3613.
    20. Narsinghani, T.; Sharma, M. C.; Bhargav, S. Synthesis, docking studies and antioxidant activity of some chalcone and aurone derivatives. Med. Chem. Res. 2013, 22, 4059-4068
    21. Haudecoeur, R.; Ahmed-Belkacem, A.; Yi, W.; Fortune, A.; Brillet, R.; Belle, C.; Nicolle, E.; Pallier, C.; Pawlotsky, J.-M.; Boumendjel, A. Discovery of naturally occurring aurones that are potent allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase. J. Med. Chem. 2011, 54, 5395-5402.
    22. Meguellati, A.; Ahmed-Belkacem, A.; Yi, W.; Haudecoeur, R.; Crouillere, M.; Brillet, R.; Pawlotsky, J.-M.; Boumendjel, A.; Peuchmaur, M. B-ring modified aurones as promising allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Eur. J. Med. Chem. 2014, 80, 579-592.
    23. Bhasker, N.; Reddy M. K. Synthesis and characterization of new series of prenyloxy chalcones, prenyloxy aurones and screening for anti-bacterial activity. Int. J. Res. Pharm. Biomed. Sci. 2011, 2, 1266-1272.
    24. Olleik, H.; Yahiaoui, S.; Roulier, B.; Courvoisier-Dezord, E.; Perrier, J.; Peres, B.; Hijazi, A.; Baydoun, E.; Raymound, J.; Boumendjel, A.; Maresca, M.; Haudecoeur, R. Aurone derivatives as promising antibacterial agents against resistant Gram-positive pathogens. Eur. J. Med. Chem. 2019, 165, 133-141.
    25. Bandgar, B. P.; Patil, S. A.; Korbad, B. L.; Biradar, S. C.; Nile, S. N.; Khobragade, C. N. Synthesis and biological evaluation of a novel series of 2,2-bisaminomethylated aurone analogues as anti-inflammatory and antimicrobial agents. Eur. J. Med. Chem. 2010, 45, 3223-3227.
    26. Souard, F.; Okombi, S.; Beney, C.; Chevalley, S.; Valentin, A.; Boumendjel, A. 1-Azaaurones derived from the naturally occurring aurones as potential antimalarial drugs. Bioorg.Med.Chem. 2010, 18, 5724-5731.
    27. Alsayari, A.; Muhsinah, A. B.; Hassan, M. Z.; Ahsan, M. J.; Alshehri, J. A.; Begum, N. Aurone: a biologically attractive scaffold as anticancer agent. Eur. J. Med. Chem. 2019, 166, 417-431.
    28. Parry, R.; Nishino, S.; Spain, J. Naturally-occurring nitro compounds. Nat. Prod. Rep. 2011, 28, 152-167.
    29. Mitra, A.; Bhowmik, S.; Ghosh, R. Preferential interaction with c-MYC quadruplex DNA mediates the cytotoxic activity of a nitro-flavone derivative in A375 cells. J. Photochem. Photobiol. 2021, 6, 100033.
    30. Inoue, J.; Ikeda, S.; Kanayama, T.; Sato, R. The flavonoid derivative 4'-nitro-6-hydroxyflavone suppresses the activity of HNF4? and stimulates the degradation of HNF4? protein through the activation of AMPK. Bosci. Biotechnol. Biochem. 2017, 81, 1548-1552.
    31. Malbari, K. D.; Chintakrindi, A. S.; Ganji, L. R.; Gohil, D. J.; Kothari, S. T.; Joshi, M. V.; Kanyalkar, M. A. Structure-aided drug development of potential neuraminidase inhibitors against pandemic H1N1 exploring alternate binding mechanism. Mol. Divers. 2019, 23, 927-951.
    32. Lu, J.-M.; Qizhi,  Y.; Chen C. 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. Biochem. Pharmacol. 2013, 86, 1328-1337.
    33. Vdovin V. S.; Lukashov S. S.; Borysenko I. P.; Fesun I. M.;  Yarmoluk S.M. The synthesis of combinatorial row of aurone derivatives as potential inhibitors of protein kinase CK2. Ukrainica Bioorganica Acta. 2015, 13, 25-31.
    34. Protopopov M.V.; Vdovin V.S.; Starosyla S.A.; Borysenko I.P.; Prykhod'ko A.O.; Lukashov S.S.; Bilokin Y.V.; Bdzhola V.G.; Yarmoluk S.M. Flavone inspired discovery of benzylidenebenzofuran-3(2H)-ones (aurones) as potent inhibitors of human protein kinase CK2. Bioorg. Chem. 2020, 102, 104062.
    35. Popova, A. V.; Bondarenko, S.P.; Frasinyuk, M. S. Aurones: synthesis and properties. Chem. Heterocycl. Comp. 2019, 55, 285-299.
    36. Turan-Zitouni, G. Fries Synthesis and structure of 2,3-dihydro-3-benzofuranamines. Chimica Acta Turcica. 1985, 13, 403-412.
    37. Enroth, C.; Eger, B. T.; Okamoto, K.; Nishino, T.; Nishino, T.; Pai, E. F. Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 10723-10728.
    38. Okamoto, K.; Eger, B. T.; Nishino, T.; Kondo, S.; Pai E. F.; Nishino, T. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J. Biol. Chem. 2003, 278, 1848-1855.
    39. Trott, O.; Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010, 31, 455.
    40. Kalckar, H. M. Differential spectrophotometry of purine compounds by means of specific enzymes: I. Determination of hydroxypurine compounds. J. Biol. Chem. 1947, 167, 429-443.
    41. Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank. Nucleic Acids Res. 2000, 28, 235-242.
    42. Huber, R.; Hof, P.; Duarte, R. O.; Moura, J. J.; Moura, I.; Liu, M. Y.; LeGall, J.; Hillw, R.; Archer, M.; Romao, M. J. A structure–based catalytic mechanism for the xanthine oxidase family of molybdenum enzymes. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 8846-8851.
    43. MarvinSketch 5.2.4, 2009, ChemAxon [Internet]. Available from: http://www.chemaxon.com (accessed on October 22, 2020).
    44. Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.; Zurek, E.; Hutchison, G. R. Avogadro: an advanced semantic chemical editor visualization, and analysis platform. J. Cheminform. 2012, 4, 17.
    45. Sanner, M. F. Python: A programming language for software integration and development. J. Mol. Graph. Model. 1999, 17, 57-61.
Full-text in PDF