Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and Biological Evaluation of 5-benzyl-3-pyridyl-1H-1,2,4-triazole Derivatives as Xanthine Oxidase Inhibitors

Author(s): Song-Ye Li , Ting-Jian Zhang , Qing-Xia Wu, Kamara M. Olounfeh, Yi Zhang and Fan-Hao Meng*

Volume 16, Issue 1, 2020

Page: [119 - 127] Pages: 9

DOI: 10.2174/1573406415666190409112209

Price: $65

Open Access Journals Promotions 2
Abstract

Background: Topiroxostat is an excellent xanthine oxidase (XO) inhibitor, possessing a specific 3,5-diaryl-1,2,4-triazole framework.

Objective: The present work was aimed to investigate the preliminary structure-activity relationship (SAR) of 2-cyanopyridine-4-yl-like fragments of topiroxostat analogues.

Methods: A series of 5-benzyl-3-pyridyl-1H-1,2,4-triazole derivatives (1a-j and 2a-j) were designed and synthesized by replacement of the 2-cyanopyridine-4-yl moiety with substituted benzyl groups. XO inhibitory activity in vitro was evaluated. Furthermore, molecular modeling simulations were performed to predict the possible interactions between the synthesized compounds and XO binding pocket.

Results: The SARs analysis demonstrated that 3,5-diaryl-1,2,4-triazole framework is not essential; in spite of its lower potency, 5-benzyl-3-pyridyl-1H-1,2,4-triazole is an acceptable scaffold for XO inhibitory activity to some extent. A 3′-nitro and a 4′-sec-butoxy group link to the benzyl moiety will be welcome. Furthermore, the most promising compound, 1h, was identified with an IC50 value of 0.16 μM, and the basis of XO inhibition by 1h was rationalized through the aid of molecular modelling studies.

Conclusion: Compound 1h could be a lead compound for further investigation and the present work may provide some insight into the search for more structurally diverse XO inhibitors with topiroxostat as a prototype.

Keywords: Topiroxostat, gout, xanthine oxidase, 1, 2, 4-triazole, pyrazoles, selenazoles.

« Previous Next »
Graphical Abstract

[1]
Ojha, R.; Singh, J.; Ojha, A.; Singh, H.; Sharma, S.; Nepali, K. An updated patent review: xanthine oxidase inhibitors for the treatment of hyperuricemia and gout (2011-2015). Expert Opin. Ther. Pat., 2017, 27(3), 311-345.
[http://dx.doi.org/10.1080/13543776.2017.1261111] [PMID: 27841045]
[2]
Kudo, M.; Moteki, T.; Sasaki, T.; Konno, Y.; Ujiie, S.; Onose, A.; Mizugaki, M.; Ishikawa, M.; Hiratsuka, M. Functional characterization of human xanthine oxidase allelic variants. Pharmacogenet. Genomics, 2008, 18(3), 243-251.
[http://dx.doi.org/10.1097/FPC.0b013e3282f55e2e] [PMID: 18300946]
[3]
Saksela, M.; Lapatto, R.; Raivio, K.O. Xanthine oxidoreductase gene expression and enzyme activity in developing human tissues. Biol. Neonate, 1998, 74(4), 274-280.
[http://dx.doi.org/10.1159/000014034] [PMID: 9701649]
[4]
Krenitsky, T.A.; Spector, T.; Hall, W.W. Xanthine oxidase from human liver: purification and characterization. Arch. Biochem. Biophys., 1986, 247(1), 108-119.
[http://dx.doi.org/10.1016/0003-9861(86)90539-4] [PMID: 3010873]
[5]
Hu, L.; Hu, H.; Wu, W.; Chai, X.; Luo, J.; Wu, Q. Discovery of novel xanthone derivatives as xanthine oxidase inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(13), 4013-4015.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.140] [PMID: 21620698]
[6]
Pacher, P.; Nivorozhkin, A.; Szabó, C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol. Rev., 2006, 58(1), 87-114.
[http://dx.doi.org/10.1124/pr.58.1.6] [PMID: 16507884]
[7]
Šmelcerović, A.; Tomović, K.; Šmelcerović, Ž.; Petronijević, Ž.; Kocić, G.; Tomašič, T.; Jakopin, Ž.; Anderluh, M. Xanthine oxidase inhibitors beyond allopurinol and febuxostat; an overview and selection of potential leads based on in silico calculated physico-chemical properties, predicted pharmacokinetics and toxicity. Eur. J. Med. Chem., 2017, 135, 491-516.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.031] [PMID: 28478180]
[8]
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(3), 1848-1855.
[http://dx.doi.org/10.1074/jbc.M208307200] [PMID: 12421831]
[9]
Ali, M.R.; Kumar, S.; Afzal, O.; Shalmali, N.; Sharma, M.; Bawa, S. Development of 2-(Substituted Benzylamino)-4-Methyl-1, 3-Thiazole-5-carboxylic acid derivatives as xanthine oxidase inhibitors and free radical scavengers. Chem. Biol. Drug Des., 2016, 87(4), 508-516.
[http://dx.doi.org/10.1111/cbdd.12686] [PMID: 26575582]
[10]
Ishibuchi, S.; Morimoto, H.; Oe, T.; Ikebe, T.; Inoue, H.; Fukunari, A.; Kamezawa, M.; Yamada, I.; Naka, Y. Synthesis and structure-activity relationships of 1-phenylpyrazoles as xanthine oxidase inhibitors. Bioorg. Med. Chem. Lett., 2001, 11(7), 879-882.
[http://dx.doi.org/10.1016/S0960-894X(01)00093-2] [PMID: 11294382]
[11]
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.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.047] [PMID: 28918097]
[12]
Guan, Q.; Cheng, Z.; Ma, X.; Wang, L.; Feng, D.; Cui, Y.; Bao, K.; Wu, L.; Zhang, W. Synthesis and bioevaluation of 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acids as potent xanthine oxidase inhibitors. Eur. J. Med. Chem., 2014, 85, 508-516.
[http://dx.doi.org/10.1016/j.ejmech.2014.08.014] [PMID: 25113879]
[13]
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.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.060] [PMID: 29407989]
[14]
Chen, S.; Zhang, T.; Wang, J.; Wang, F.; Niu, H.; Wu, C.; Wang, S. Synthesis and evaluation of 1-hydroxy/methoxy-4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid derivatives as non-purine xanthine oxidase inhibitors. Eur. J. Med. Chem., 2015, 103, 343-353.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.056] [PMID: 26363870]
[15]
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(16), 3812-3816.
[http://dx.doi.org/10.1016/j.bmcl.2017.06.059] [PMID: 28693909]
[16]
Song, J.U.; Choi, S.P.; Kim, T.H.; Jung, C-K.; Lee, J-Y.; Jung, S-H.; Kim, G.T. Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors. Bioorg. Med. Chem. Lett., 2015, 25(6), 1254-1258.
[http://dx.doi.org/10.1016/j.bmcl.2015.01.055] [PMID: 25704891]
[17]
Song, J.U.; Jang, J.W.; Kim, T.H.; Park, H.; Park, W.S.; Jung, S.H.; Kim, G.T. Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(3), 950-954.
[http://dx.doi.org/10.1016/j.bmcl.2015.12.055] [PMID: 26774578]
[18]
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(6), 2663-2670.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.013] [PMID: 20189693]
[19]
Zhang, T.J.; Li, S.Y.; Yuan, W.Y.; Wu, Q.X.; Wang, L.; Yang, S.; Sun, Q.; Meng, F.H. Discovery and biological evaluation of some (1H-1,2,3-triazol-4-yl)methoxybenzaldehyde derivatives containing an anthraquinone moiety as potent xanthine oxidase inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(4), 729-732.
[http://dx.doi.org/10.1016/j.bmcl.2017.01.049] [PMID: 28131711]
[20]
Zhang, T.J.; Li, S.Y.; Yuan, W.Y.; Zhang, Y.; Meng, F.H. Design, synthesis, and molecular docking studies of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives as xanthine oxidase inhibitors. Chem. Biol. Drug Des., 2018, 91(4), 893-901.
[http://dx.doi.org/10.1111/cbdd.13156] [PMID: 29197158]
[21]
Shi, D-H.; Huang, W.; Li, C.; Liu, Y-W.; Wang, S-F. Design, synthesis and molecular modeling of aloe-emodin derivatives as potent xanthine oxidase inhibitors. Eur. J. Med. Chem., 2014, 75, 289-296.
[http://dx.doi.org/10.1016/j.ejmech.2014.01.058] [PMID: 24556143]
[22]
B-Rao, C.; Kulkarni-Almeida, A.; Katkar, K. V. Khanna, S.; Ghosh, U.; Keche, A.; Shah, P.; Srivastava, A.; Korde, V.; Nemmani, K. V. S.; Deshmukh, N. J.; Dixit, A.; Brahma, M. K.; Bahirat, U.; Doshi, L.; Sharma, R.; Sivaramakrishnan, H., . Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits. Bioorg. Med. Chem., 2012, 20, 2930-2939.
[23]
Evenäs, J.; Edfeldt, F.; Lepistö, M.; Svitacheva, N.; Synnergren, A.; Lundquist, B.; Gränse, M.; Rönnholm, A.; Varga, M.; Wright, J.; Wei, M.; Yue, S.; Wang, J.; Li, C.; Li, X.; Chen, G.; Liao, Y.; Lv, G.; Tjörnebo, A.; Narjes, F. HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase. Bioorg. Med. Chem. Lett., 2014, 24(5), 1315-1321.
[http://dx.doi.org/10.1016/j.bmcl.2014.01.050] [PMID: 24508129]
[24]
Santi, M.D.; Paulino Zunini, M.; 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.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.071] [PMID: 29207340]
[25]
Nile, S.H.; Keum, Y.S.; Nile, A.S.; Jalde, S.S.; Patel, R.V. Antioxidant, anti-inflammatory, and enzyme inhibitory activity of natural plant flavonoids and their synthesized derivatives. J. Biochem. Mol. Toxicol., 2018, 32(1)e22002
[http://dx.doi.org/10.1002/jbt.22002] [PMID: 28972678]
[26]
de Araújo, M.E.M.B.; Franco, Y.E.M.; Alberto, T.G.; Messias, M.C.F.; Leme, C.W.; Sawaya, A.C.H.F.; Carvalho, P.O. Kinetic study on the inhibition of xanthine oxidase by acylated derivatives of flavonoids synthesised enzymatically. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 978-985.
[http://dx.doi.org/10.1080/14756366.2017.1347165] [PMID: 28718686]
[27]
Matsumoto, K.; Okamoto, K.; Ashizawa, N.; Nishino, T. FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase. J. Pharmacol. Exp. Ther., 2011, 336(1), 95-103.
[http://dx.doi.org/10.1124/jpet.110.174540] [PMID: 20952484]
[28]
Zhang, T.J.; Li, S.Y.; Zhang, Y.; Wu, Q.X.; Meng, F.H. Design, synthesis, and biological evaluation of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives as xanthine oxidase inhibitors. Chem. Biol. Drug Des., 2018, 91(2), 526-533.
[http://dx.doi.org/10.1111/cbdd.13114] [PMID: 28950055]
[29]
Sato, T.; Ashizawa, N.; Iwanaga, T.; Nakamura, H.; Matsumoto, K.; Inoue, T.; Nagata, O. Design, synthesis, and pharmacological and pharmacokinetic evaluation of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(1), 184-187.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.122] [PMID: 19027292]
[30]
Zhang, T.J.; Li, S.Y.; Wang, L.; Sun, Q.; Wu, Q.X.; Zhang, Y.; Meng, F.H. Design, synthesis and biological evaluation of N-(4-alkoxy-3-cyanophenyl)isonicotinamide/nicotinamide derivatives as novel xanthine oxidase inhibitors. Eur. J. Med. Chem., 2017, 141, 362-372.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.051] [PMID: 29032030]
[31]
Abbas, S.H. Abuo-Rahma, Gel-D.; Abdel-Aziz, M.; Aly, O.M.; Beshr, E.A.; Gamal-Eldeen, A.M. Synthesis, cytotoxic activity, and tubulin polymerization inhibitory activity of new pyrrol-2(3H)-ones and pyridazin-3(2H)-ones. Bioorg. Chem., 2016, 66, 46-62.
[http://dx.doi.org/10.1016/j.bioorg.2016.03.007] [PMID: 27016713]

Rights & Permissions Print Cite
Article Metrics
38
2
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy