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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Research Article

Design, Synthesis, and Biological Activity of a Novel Series of 2-Ureidonicotinamide Derivatives Against Influenza A Virus

Author(s): Chao Zhang, Jun-Jie Xiang, Jing Zhao, Yan-Li Meng, Fu-Rong Zhang, Zhe Jin, Pang-Chui Shaw, Xiao-Ping Liu* and Chun Hu*

Volume 29, Issue 26, 2022

Published on: 17 May, 2022

Page: [4610 - 4627] Pages: 18

DOI: 10.2174/0929867329666220224114627

Price: $65

Abstract

Background: Viral resistance to existing inhibitors and the time-dependent effectiveness of neuraminidase inhibitors have limited the number of antivirals that can be used for prophylaxis and therapeutic treatment of severe influenza infection. Thus, there is an urgent need to develop new drugs to prevent and treat influenza infection.

Objective: The aims of this study was to design and synthesize a novel series of 2-ureidonicotinamide derivatives and evaluate their anti-IAV activities. Furthermore, we predicted the abilities of these compounds to inhibit the PA-PB1 subunit and forecasted the docking poses of these compounds with RNA polymerase protein (PDB ID 3CM8).

Methods: The novel designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their abilities inhibiting RNP and against influenza A virus. In addition, the 23 synthesized molecules were subjected to the generated pharmacophore Hypo1 to forecast the activity target PA-PB1 subunit of RNA polymerase. The ADMET pharmacokinetic parameters were calculated by the ADMET modules in Discovery Studio 2016. The docking results helped us demonstrate the possible interactions between these compounds with 3CM8.

Results: The synthesized 2-ureidonicotinamide derivatives were characterized as potent anti-influenza inhibitors. The target compounds 7b and 7c demonstrated significant antiviral activities and could be considered as novel lead compounds of antiviral inhibitors. In addition, compound 7b revealed suitable ADME properties expressed and might be a significant RNA polymerase inhibitor targeting the PA-PB1 subunit based on the predictable results and the docking results.

Conclusion: This study revealed a novel series of compounds that might be useful in the search for an effective drug against the influenza virus.

Keywords: Influenza virus, RNA-dependent RNA polymerase, 2-ureidonicotinamide derivatives, antiviral inhibitors, PA-PB1 subunit, inhibition of RNP activities.

« Previous
[1]
Ju, H.; Zhang, J.; Huang, B.; Kang, D.; Huang, B.; Liu, X.; Zhan, P. Inhibitors of influenza virus polymerase acidic (PA) endonuclease: contemporary developments and perspectives. J. Med. Chem., 2017, 60(9), 3533-3551.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01227] [PMID: 28118010]
[2]
Gao, R.; Cao, B.; Hu, Y.; Feng, Z.; Wang, D.; Hu, W.; Chen, J.; Jie, Z.; Qiu, H.; Xu, K.; Xu, X.; Lu, H.; Zhu, W.; Gao, Z.; Xiang, N.; Shen, Y.; He, Z.; Gu, Y.; Zhang, Z.; Yang, Y.; Zhao, X.; Zhou, L.; Li, X.; Zou, S.; Zhang, Y.; Li, X.; Yang, L.; Guo, J.; Dong, J.; Li, Q.; Dong, L.; Zhu, Y.; Bai, T.; Wang, S.; Hao, P.; Yang, W.; Zhang, Y.; Han, J.; Yu, H.; Li, D.; Gao, G.F.; Wu, G.; Wang, Y.; Yuan, Z.; Shu, Y. Human infection with a novel avian-origin influenza A (H7N9) virus. N. Engl. J. Med., 2013, 368(20), 1888-1897.
[http://dx.doi.org/10.1056/NEJMoa1304459] [PMID: 23577628]
[3]
Neumann, G.; Noda, T.; Kawaoka, Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature, 2009, 459(7249), 931-939.
[http://dx.doi.org/10.1038/nature08157] [PMID: 19525932]
[4]
Bright, R.A.; Shay, D.K.; Shu, B.; Cox, N.J.; Klimov, A.I. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA, 2006, 295(8), 891-894.
[http://dx.doi.org/10.1001/jama.295.8.joc60020] [PMID: 16456087]
[5]
Collins, P.J.; Haire, L.F.; Lin, Y.P.; Liu, J.; Russell, R.J.; Walker, P.A.; Skehel, J.J.; Martin, S.R.; Hay, A.J.; Gamblin, S.J. Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature, 2008, 453(7199), 1258-1261.
[http://dx.doi.org/10.1038/nature06956] [PMID: 18480754]
[6]
Moscona, A. Global transmission of oseltamivir-resistant influenza. N. Engl. J. Med., 2009, 360(10), 953-956.
[http://dx.doi.org/10.1056/NEJMp0900648] [PMID: 19258250]
[7]
Du, J.; Cross, T.A.; Zhou, H.X. Recent progress in structure-based anti-influenza drug design. Drug Discov. Today, 2012, 17(19-20), 1111-1120.
[http://dx.doi.org/10.1016/j.drudis.2012.06.002] [PMID: 22704956]
[8]
Dunning, J.; Baillie, J.K.; Cao, B.; Hayden, F.G. Antiviral combinations for severe influenza. Lancet Infect. Dis., 2014, 14(12), 1259-1270.
[http://dx.doi.org/10.1016/S1473-3099(14)70821-7] [PMID: 25213733]
[9]
Sidwell, R.W.; Smee, D.F. Peramivir (BCX-1812, RWJ-270201): potential new therapy for influenza. Expert Opin. Investig. Drugs, 2002, 11(6), 859-869.
[http://dx.doi.org/10.1517/13543784.11.6.859] [PMID: 12036429]
[10]
Cheng, C.K.; Tsai, C.H.; Shie, J.J.; Fang, J.M. From neuraminidase inhibitors to conjugates: a step towards better anti-influenza drugs? Future Med. Chem., 2014, 6(7), 757-774.
[http://dx.doi.org/10.4155/fmc.14.30] [PMID: 24941871]
[11]
Watanabe, T.; Kawaoka, Y. Influenza virus-host interactomes as a basis for antiviral drug development. Curr. Opin. Virol., 2015, 14, 71-78.
[http://dx.doi.org/10.1016/j.coviro.2015.08.008] [PMID: 26364134]
[12]
Kormuth, K.A.; Lakdawala, S.S. Emerging antiviral resistance. Nat. Microbiol., 2020, 5(1), 4-5.
[http://dx.doi.org/10.1038/s41564-019-0639-7] [PMID: 31857727]
[13]
Xiao, M.; Xu, L.; Lin, D.; Lian, W.; Cui, M.; Zhang, M.; Yan, X.; Li, S.; Zhao, J.; Ye, J.; Liu, A.; Hu, A. Design, synthesis, and bioassay of 4-thiazolinone derivatives as influenza neuraminidase inhibitors. Eur. J. Med. Chem., 2021, 213, 113161.
[http://dx.doi.org/10.1016/j.ejmech.2021.113161] [PMID: 33540229]
[14]
Li, L.; Chang, S.H.; Xiang, J.F.; Li, Q.; Liang, H.H.; Tang, Y.L.; Liu, Y.F. NMR identification of anti-influenza lead compound targeting at PAC subunit of H5N1 polymerase. Chin. Chem. Lett., 2012, 23(1), 89-92.
[http://dx.doi.org/10.1016/j.cclet.2011.09.006]
[15]
Amarelle, L.; Lecuona, E.; Sznajder, J.I. Anti-influenza treatment: drugs currently used and under development. Arch. Bronconeumol., 2017, 53(1), 19-26.
[http://dx.doi.org/10.1016/j.arbr.2016.11.020] [PMID: 27519544]
[16]
Huang, T.S.; Palese, P.; Krystal, M. Determination of influenza virus proteins required for genome replication. J. Virol., 1990, 64(11), 5669-5673.
[http://dx.doi.org/10.1128/jvi.64.11.5669-5673.1990] [PMID: 2214032]
[17]
Kashiwagi, T.; Hara, K.; Nakazono, Y.; Uemura, Y.; Imamura, Y.; Hamada, N.; Watanabe, H. The N-terminal fragment of a PB2 subunit from the influenza A virus (A/Hong Kong/156/1997 H5N1) effectively inhibits RNP activity and viral replication. PLoS One, 2014, 9(12), e114502/1-e114502/17.
[http://dx.doi.org/10.1371/journal.pone.0114502]
[18]
Yuan, S.; Wen, L.; Zhou, J. Inhibitors of influenza a virus polymerase. ACS Infect. Dis., 2018, 4(3), 218-223.
[http://dx.doi.org/10.1021/acsinfecdis.7b00265] [PMID: 29355011]
[19]
Kao, R.Y.; Yang, D.; Lau, L.S.; Tsui, W.H.W.; Hu, L.; Dai, J.; Chan, M.P.; Chan, C.M.; Wang, P.; Zheng, B.J.; Sun, J.; Huang, J.D.; Madar, J.; Chen, G.; Chen, H.; Guan, Y.; Yuen, K.Y. Identification of influenza A nucleoprotein as an antiviral target. Nat. Biotechnol., 2010, 28(6), 600-605.
[http://dx.doi.org/10.1038/nbt.1638] [PMID: 20512121]
[20]
Furuta, Y.; Gowen, B.B.; Takahashi, K.; Shiraki, K.; Smee, D.F.; Barnard, D.L. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res., 2013, 100(2), 446-454.
[http://dx.doi.org/10.1016/j.antiviral.2013.09.015] [PMID: 24084488]
[21]
Li, T.C.; Chan, M.C.; Lee, N. Clinical implications of antiviral resistance in influenza. Viruses, 2015, 7(9), 4929-4944.
[http://dx.doi.org/10.3390/v7092850] [PMID: 26389935]
[22]
Titova, Y.A.; Fedorova, O.V. Favipiravir-a modern antiviral drug: synthesis and modifications. Chem. Heterocycl. Compd., 2020, 56(6), 1-4.
[http://dx.doi.org/10.1007/s10593-020-02715-3] [PMID: 32836314]
[23]
Gribble, G.W.; Fletcher, G.L.; Ketcha, D.M.; Rajopadhye, M. Metalated heterocycles in the synthesis of ellipticine analogues: A new route to the 10H-pyrido[2,3-b]carbazole ring system. J. Org. Chem., 1989, 54(14), 3264-3269.
[http://dx.doi.org/10.1021/jo00275a008]
[24]
Spiessens, L.I.M.; Anteunis, M.J.O. Preparation and structural assignments of some isomeric 2,3-disubstituted pyridines. Bull. Soc. Chim. Belg., 1980, 89(3), 205-231.
[http://dx.doi.org/10.1002/bscb.19840930306]
[25]
Robins, R.K.; Hitchings, G.H. Condensed pyrimidine systems. XII. Synthesis of some 4- and 2,4-substituted pyrido[2,3-d]pyrimidines. J. Am. Chem. Soc., 1955, 77(8), 2256-2260.
[http://dx.doi.org/10.1021/ja01613a069]
[26]
Fodor, E.; Devenish, L.; Engelhardt, O.G.; Palese, P.; Brownlee, G.G.; García-Sastre, A. Rescue of influenza A virus from recombinant DNA. J. Virol., 1999, 73(11), 9679-9682.
[http://dx.doi.org/10.1128/JVI.73.11.9679-9682.1999] [PMID: 10516084]
[27]
Fodor, E.; Crow, M.; Mingay, L.J.; Deng, T.; Sharps, J.; Fechter, P.; Brownlee, G.G. A single amino acid mutation in the PA subunit of the influenza virus RNA polymerase inhibits endonucleolytic cleavage of capped RNAs. J. Virol., 2002, 76(18), 8989-9001.
[http://dx.doi.org/10.1128/JVI.76.18.8989-9001.2002] [PMID: 12186883]
[28]
Li, O.T.W.; Chan, M.C.W.; Leung, C.S.W.; Chan, R.W.Y.; Guan, Y.; Nicholls, J.M.; Poon, L.L.M. Full factorial analysis of mammalian and avian influenza polymerase subunits suggests a role of an efficient polymerase for virus adaptation. PLoS One, 2009, 4(5), e5658.
[http://dx.doi.org/10.1371/journal.pone.0005658] [PMID: 19462010]
[29]
Lo, C.Y.; Li, O.T.W.; Tang, W.P.; Hu, C.; Wang, G.X.; Ngo, J.C.K.; Wan, D.C.C.; Poon, L.L.M.; Shaw, P.C. Identification of influenza polymerase inhibitors targeting C-terminal domain of PA through surface plasmon resonance screening. Sci. Rep., 2018, 8(1), 2280.
[http://dx.doi.org/10.1038/s41598-018-20772-9] [PMID: 29396435]
[30]
Wang, Y.; Yan, W.; Chen, Q.; Huang, W.; Yang, Z.; Li, X.; Wang, X. Inhibition viral RNP and anti-inflammatory activity of coumarins against influenza virus. Biomed. Pharmacother., 2017, 87, 583-588.
[http://dx.doi.org/10.1016/j.biopha.2016.12.117] [PMID: 28081470]
[31]
Zhang, T.; Xiao, M.; Wong, C.K.; Mok, K.C.; Zhao, X.; Ti, H.; Shaw, P.C.; Sheng, J.S. A traditional multi-herb formulation, exerts anti-influenza effects in vitro and in vivo via neuraminidase inhibition and immune regulation. BMC Complement. Altern. Med., 2018, 18(1), 150.
[http://dx.doi.org/10.1186/s12906-018-2216-7] [PMID: 29739459]
[32]
Massari, S.; Nannetti, G.; Desantis, J.; Muratore, G.; Sabatini, S.; Manfroni, G.; Mercorelli, B.; Cecchetti, V.; Palù, G.; Cruciani, G.; Loregian, A.; Goracci, L.; Tabarrini, O. A broad anti-influenza hybrid small molecule that potently disrupts the interaction of polymerase acidic protein–basic protein 1 (PA-PB1) subunits. J. Med. Chem., 2015, 58(9), 3830-3842.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00012] [PMID: 25856229]
[33]
Massari, S.; Bertagnin, C.; Pismataro, M.C.; Donnadio, A.; Nannetti, G.; Felicetti, T.; Di Bona, S.; Nizi, M.G.; Tensi, L.; Manfroni, G.; Loza, M.I.; Sabatini, S.; Cecchetti, V.; Brea, J.; Goracci, L.; Loregian, A.; Tabarrini, O. Synthesis and characterization of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide-based compounds targeting the PA-PB1 interface of influenza A virus polymerase. Eur. J. Med. Chem., 2021, 209, 112944.
[http://dx.doi.org/10.1016/j.ejmech.2020.112944] [PMID: 33328103]
[34]
Lepri, S.; Nannetti, G.; Muratore, G.; Cruciani, G.; Ruzziconi, R.; Mercorelli, B.; Palù, G.; Loregian, A.; Goracci, L. Optimization of small-molecule inhibitors of influenza virus polymerase: from thiophene-3-carboxamide to polyamido scaffolds. J. Med. Chem., 2014, 57(10), 4337-4350.
[http://dx.doi.org/10.1021/jm500300r] [PMID: 24785979]
[35]
Massari, S.; Goracci, L.; Desantis, J.; Tabarrini, O. Polymerase acidic protein–basic protein 1 (PA–PB1) protein–protein interaction as a target for next-generation anti-influenza therapeutics. J. Med. Chem., 2016, 59(17), 7699-7718.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01474] [PMID: 27046062]
[36]
Desantis, J.; Nannetti, G.; Massari, S.; Barreca, M.L.; Manfroni, G.; Cecchetti, V.; Palù, G.; Goracci, L.; Loregian, A.; Tabarrini, O. Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity. Eur. J. Med. Chem., 2017, 138, 128-139.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.015] [PMID: 28666191]
[37]
Tintori, C.; Laurenzana, I.; Fallacara, A.L.; Kessler, U.; Pilger, B.; Stergiou, L.; Botta, M. High-throughput docking for the identification of new influenza A virus polymerase inhibitors targeting the PA-PB1 protein-protein interaction. Bioorg. Med. Chem. Lett., 2014, 24(1), 280-282.
[http://dx.doi.org/10.1016/j.bmcl.2013.11.019] [PMID: 24314669]
[38]
D’Agostino, I.; Giacchello, I.; Nannetti, G.; Fallacara, A.L.; Deodato, D.; Musumeci, F.; Grossi, G.; Palù, G.; Cau, Y.; Trist, I.M.; Loregian, A.; Schenone, S.; Botta, M. Synthesis and biological evaluation of a library of hybrid derivatives as inhibitors of influenza virus PA-PB1 interaction. Eur. J. Med. Chem., 2018, 157, 743-758.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.032] [PMID: 30142611]
[39]
He, X.; Zhou, J.; Bartlam, M.; Zhang, R.; Ma, J.; Lou, Z.; Li, X.; Li, J.; Joachimiak, A.; Zeng, Z.; Ge, R.; Rao, Z.; Liu, Y. Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus. Nature, 2008, 454(7208), 1123-1126.
[http://dx.doi.org/10.1038/nature07120] [PMID: 18615018]
[40]
Yuan, S.; Chu, H.; Ye, J.; Singh, K.; Ye, Z.; Zhao, H.; Kao, R.Y.T.; Chow, B.K.C.; Zhou, J.; Zheng, B.J. Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface. Antiviral Res., 2017, 137, 58-66.
[http://dx.doi.org/10.1016/j.antiviral.2016.11.005] [PMID: 27840201]
[41]
Tkachuk, V.; Merkulova, V.; Omelchenko, I.; Arrault, A.; Hordiyenko, O. Cyclic acyl amidines as unexpected C4-donors for fully substituted pyridine ring formation in the base mediated reaction with malononitrile. Tetrahedron Lett., 2019, 60(30), 1959-1963.
[http://dx.doi.org/10.1016/j.tetlet.2019.06.038]
[42]
Zhu, Y.; Chen, X.; Ran, T.; Niu, J.; Zhao, S.; Lu, T.; Tang, W. Design, synthesis and biological evaluation of urea-based benzamides derivatives as HDAC inhibitors. Med. Chem. Res., 2017, 26(11), 2879-2888.
[http://dx.doi.org/10.1007/s00044-017-1987-6]
[43]
Kodama, K.; Morita, R.; Hirose, T. Formation of ternary inclusion crystal and enantioseparation of alkyl aryl sulfoxides by the salt of urea-modified L-phenylalanine and an achiral amine. Cryst. Growth Des., 2016, 16(9), 5206-5213.
[http://dx.doi.org/10.1021/acs.cgd.6b00768]
[44]
Liu, Y.Y.; Feng, X.Y.; Jia, W.Q.; Jing, Z.; Xu, W.R.; Cheng, X.C. Identification of novel PI3Kδ inhibitors by docking, ADMET prediction and molecular dynamics simulations. Comput. Biol. Chem., 2019, 78, 190-204.
[http://dx.doi.org/10.1016/j.compbiolchem.2018.12.002] [PMID: 30557817]
[45]
Mondal, S.K.; Mondal, N.B.; Banerjee, S.; Mazumder, U.K. Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies. Indian J. Pharmacol., 2009, 41(4), 176-181.
[http://dx.doi.org/10.4103/0253-7613.56075] [PMID: 20523869]
[46]
Yasmin, S.; Mhlongo, N.N.; Soliman, M.E.; Saraswathi, G.R.; Jayaprakash, V. Comparative design, in silico docking and predictive ADME/TOX properties of some novel 2, 4-hydroxy derivatives of thiazolidine-2,4-diones as PPARγ modulator. J. Pharm. Chem, 2017, 4(2), 11-19.
[http://dx.doi.org/10.14805/jphchem.2017.art74]
[47]
Reich, S.; Guilligay, D.; Pflug, A.; Malet, H.; Berger, I.; Crépin, T.; Hart, D.; Lunardi, T.; Nanao, M.; Ruigrok, R.W.H.; Cusack, S. Structural insight into cap-snatching and RNA synthesis by influenza polymerase. Nature, 2014, 516(7531), 361-366.
[http://dx.doi.org/10.1038/nature14009] [PMID: 25409151]
[48]
Aier, I.; Varadwaj, P.K.; Raj, U. Structural insights into conformational stability of both wild-type and mutant EZH2 receptor. Sci. Rep., 2016, 6(1), 34984.
[http://dx.doi.org/10.1038/srep34984] [PMID: 27713574]
[49]
Obayashi, E.; Yoshida, H.; Kawai, F.; Shibayama, N.; Kawaguchi, A.; Nagata, K.; Tame, J.R.H.; Park, S.Y. The structural basis for an essential subunit interaction in influenza virus RNA polymerase. Nature, 2008, 454(7208), 1127-1131.
[http://dx.doi.org/10.1038/nature07225] [PMID: 18660801]
[50]
Yuan, S.; Chan, H.C.S.; Filipek, S.; Vogel, H. PyMOL and inkscape bridge the data and the data visualization. Structure, 2016, 24(12), 2041-2042.
[http://dx.doi.org/10.1016/j.str.2016.11.012] [PMID: 27926832]
[51]
Trist, I.M.L.; Nannetti, G.; Tintori, C.; Fallacara, A.L.; Deodato, D.; Mercorelli, B.; Palù, G.; Wijtmans, M.; Gospodova, T.; Edink, E.; Verheij, M.; de Esch, I.; Viteva, L.; Loregian, A.; Botta, M. 4,6-diphenyl pyridines as promising novel anti-influenza agents targeting the PA-PB1 protein-protein interaction: structure-activity relationships exploration with the aid of molecular modeling. J. Med. Chem., 2016, 59(6), 2688-2703.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01935] [PMID: 26924568]

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