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Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Design, Synthesis, Inhibitory Activity, and SAR Studies of Hydrophobic Phenylacetic Acid Derivatives as Neuraminidase Inhibitors

Author(s): Chanmei Lv and Fangyuan Shi*

Volume 20, Issue 7, 2023

Published on: 02 August, 2022

Page: [821 - 831] Pages: 11

DOI: 10.2174/1570180819666220517094622

Price: $65

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Abstract

Introduction: A series of hydrophobic phenylacetic acid derivatives introducing an aromatic lipophilic side chain at C-3 amino and an acetyl or isopropionyl at C-4 amino were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus.

Methods: All compounds were synthesized in good yields starting from commercially available 2-(4- aminophenyl) acetic acid using a suitable synthetic strategy.

Results: These compounds showed potent inhibitory activity against influenza A NA. Several compounds with alkylated amino group showed moderate NA subtype selectivity, among which compound (7i) displayed the best.

Conclusion: Compound (7i) activity against H5N1 was more than 10 times better than H9N2, and could be used as lead compounds in the future.

Keywords: Influenza virus, neuraminidase, phenylacetic acid, inhibitors, rational drug design, structure-activity.

Graphical Abstract

[1]
Pennisi, E. Planning for the next flu pandemic. Science, 1995, 270(5244), 1916-1917.
[http://dx.doi.org/10.1126/science.270.5244.1916] [PMID: 8533078]
[2]
Iuliano, A.D.; Roguski, K.M.; Chang, H.H.; Muscatello, D.J.; Palekar, R.; Tempia, S.; Cohen, C.; Gran, J.M.; Schanzer, D.; Cowling, B.J.; Wu, P.; Kyncl, J.; Ang, L.W.; Park, M.; Redlberger-Fritz, M.; Yu, H.; Espenhain, L.; Krishnan, A.; Emukule, G.; van Asten, L.; Pereira da Silva, S.; Aungkulanon, S.; Buchholz, U.; Widdowson, M.A.; Bresee, J.S.; Azziz-Baumgartner, E.; Cheng, PY.; Dawood, F.; Foppa, I.; Olsen, S.; Haber, M.; Jeffers, C.; Mac-Intyre, C.R.; Newall, A.T.; Wood, J.G.; Kundi, M.; Popow-Kraupp, T.; Ahmed, M.; Rahman, M.; Marinho, F.; Sotomayor Proschle, C.V.; Vergara Mallegas, N.; Luzhao, F.; Sa, L.; Barbosa-Ramírez, J.; Sanchez, D.M.; Gomez, L.A.; Vargas, X.B.; Acosta Herrera, B.; Llanés, M.J.; Fischer, T.K.; Krause, T.G.; Mølbak, K.; Nielsen, J.; Trebbien, R.; Bruno, A.; Ojeda, J.; Ramos, H.; an der Heiden, M.; del Carmen Castillo Signor, L.; Serrano, C.E.; Bhardwaj, R.; Chadha, M.; Narayan, V.; Kosen, S.; Bromberg, M.; Glatman-Freedman, A.; Kaufman, Z.; Arima, Y.; Oishi, K.; Chaves, S.; Nyawanda, B.; Al-Jarallah, R.A.; Kuri-Morales, P.A.; Matus, C.R.; Corona, M.E.J.; Burmaa, A.; Darmaa, O.; Obtel, M.; Cherkaoui, I.; van den Wijngaard, C.C.; van der Hoek, W.; Baker, M.; Bandaranayake, D.; Bissielo, A.; Huang, S.; Lopez, L.; Newbern, C.; Flem, E.; Grøneng, G.M.; Hauge, S.; de Cosío, F.G.; de Moltó, Y.; Castillo, L.M.; Cabello, M.A.; von Horoch, M.; Medina Osis, J.; Machado, A.; Nunes, B.; Rodrigues, A.P.; Rodrigues, E.; Calomfirescu, C.; Lupulescu, E.; Popescu, R.; Popovici, O.; Bogdanovic, D.; Kostic, M.; Lazarevic, K.; Milosevic, Z.; Tiodorovic, B.; Chen, M.; Cutter, J.; Lee, V.; Lin, R.; Ma, S.; Cohen, A.L.; Treurnicht, F.; Kim, W.J.; Delgado-Sanz, C.; de mateo Ontañón, S.; Larrauri, A.; León, I.L.; Vallejo, F.; Born, R.; Junker, C.; Koch, D.; Chuang, J-H.; Huang, W-T.; Kuo, H-W.; Tsai, Y-C.; Bundhamcharoen, K.; Chittaganpitch, M.; Green, H.K.; Pebody, R.; Goñi, N.; Chiparelli, H.; Brammer, L.; Mustaquim, D. Estimates of global seasonal influenza-associated respiratory mortality: A modelling study. Lancet, 2018, 391(10127), 1285-1300.
[http://dx.doi.org/10.1016/S0140-6736(17)33293-2] [PMID: 29248255]
[3]
Wang, X.; Li, Y.; O’Brien, K.L.; Madhi, S.A.; Widdowson, M.A.; Byass, P.; Omer, S.B.; Abbas, Q.; Ali, A.; Amu, A.; Azziz-Baumgartner, E.; Bassat, Q.; Abdullah Brooks, W.; Chaves, S.S.; Chung, A.; Cohen, C.; Echavarria, M.; Fasce, R.A.; Gentile, A.; Gordon, A.; Groome, M.; Heikkinen, T.; Hirve, S.; Jara, J.H.; Katz, M.A.; Khuri-Bulos, N.; Krishnan, A.; de Leon, O.; Lucero, M.G.; McCracken, J.P.; Mira-Iglesias, A.; Moïsi, J.C.; Munywoki, P.K.; Ourohiré, M.; Polack, F.P.; Rahi, M.; Rasmussen, Z.A.; Rath, B.A.; Saha, S.K.; Simões, E.A.; Sotomayor, V.; Thamthitiwat, S.; Treurnicht, F.K.; Wamukoya, M.; Yoshida, L.M.; Zar, H.J.; Campbell, H.; Nair, H.; Respiratory Virus Global Epidemiology, N. Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: A systematic review and modelling study. Lancet Glob. Health, 2020, 8(4), e497-e510.
[http://dx.doi.org/10.1016/S2214-109X(19)30545-5] [PMID: 32087815]
[4]
Credille, C.V.; Morrison, C.N.; Stokes, R.W.; Dick, B.L.; Feng, Y.; Sun, J.; Chen, Y.; Cohen, S.M. SAR exploration of tight-binding inhibitors of influenza virus PA endonuclease. J. Med. Chem., 2019, 62(21), 9438-9449.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00747] [PMID: 31536340]
[5]
O’Hanlon, R.; Shaw, M.L. Baloxavir marboxil: The new influenza drug on the market. Curr. Opin. Virol., 2019, 35, 14-18.
[http://dx.doi.org/10.1016/j.coviro.2019.01.006] [PMID: 30852344]
[6]
Uyeki, T.M.; Bernstein, H.H.; Bradley, J.S.; Englund, J.A.; File, T.M., Jr; Fry, A.M.; Gravenstein, S.; Hayden, F.G.; Harper, S.A.; Hirshon, J.M.; Ison, M.G.; Johnston, B.L.; Knight, S.L.; McGeer, A.; Riley, L.E.; Wolfe, C.R.; Alexander, P.E.; Pavia, A.T. Clinical practice guidelines by the infectious diseases society of america: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenzaa. Clin. Infect. Dis., 2019, 68(6), e1-e47.
[http://dx.doi.org/10.1093/cid/ciy866] [PMID: 30566567]
[7]
Monod, A.; Swale, C.; Tarus, B.; Tissot, A.; Delmas, B.; Ruigrok, R.W.; Crépin, T.; Slama-Schwok, A. Learning from structure-based drug design and new antivirals targeting the ribonucleoprotein complex for the treatment of influenza. Expert Opin. Drug Discov., 2015, 10(4), 345-371.
[http://dx.doi.org/10.1517/17460441.2015.1019859] [PMID: 25792362]
[8]
Zhang, J.; Wang, Q.; Fang, H.; Xu, W.; Liu, A.; Du, G. Design, synthesis, inhibitory activity, and SAR studies of hydrophobic p-aminosalicylic acid derivatives as neuraminidase inhibitors. Bioorg. Med. Chem., 2008, 16(7), 3839-3847.
[http://dx.doi.org/10.1016/j.bmc.2008.01.036] [PMID: 18304821]
[9]
Xie, Y.; Huang, B.; Yu, K.; Shi, F.; Liu, T.; Xu, W. Caffeic acid derivatives: A new type of influenza neuraminidase inhibitors. Bioorg. Med. Chem. Lett., 2013, 23(12), 3556-3560.
[http://dx.doi.org/10.1016/j.bmcl.2013.04.033] [PMID: 23664211]
[10]
Shi, F.; Fang, H.; Wenfang, X.U. Design, synthesis and biological activity of novel chalcone derivatives as anti-influenza agents. Chem. Res. Chin. Univ., 2016, 32(001), 28-34.
[http://dx.doi.org/10.1007/s40242-015-5356-z]
[11]
Xie, Y.; Xu, D.; Huang, B.; Ma, X.; Qi, W.; Shi, F.; Liu, X.; Zhang, Y.; Xu, W. Discovery of N-substituted oseltamivir derivatives as potent and selective inhibitors of H5N1 influenza neuraminidase. J. Med. Chem., 2014, 57(20), 8445-8458.
[http://dx.doi.org/10.1021/jm500892k] [PMID: 25255388]
[12]
Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature,
[http://dx.doi.org/10.1038/s41586-020-2180-5]
[13]
Singh, S.; Jedrzejas, M.J.; Air, G.M.; Luo, M.; Laver, W.G.; Brouillette, W.J. Structure-based inhibitors of influenza virus sialidase. A benzoic acid lead with novel interaction. J. Med. Chem., 1995, 38(17), 3217-3225.
[http://dx.doi.org/10.1021/jm00017a005] [PMID: 7650674]

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