Abstract
Zika virus (ZIKV), an arbovirus of the Flaviviridae family, has emerged as a significant public health concern owing to its association with congenital abnormalities and severe neurological sequelae. Thus, there is an urgent need to develop effective therapeutic approaches to efficiently treat ZIKV infections. This study used phenotypic screening to identify a series of 1,2,4-oxadiazole derivatives that possess antiviral activity against ZIKV infection. Subsequently, 28 new derivatives were designed, synthesized, and evaluated for this purpose. Among these compounds, 4-(5-phenyl-1,2,4-oxadiazol-3-yl)-N-(pyridin-3-ylmethyl)aniline (5d) had potent antiviral activity against ZIKV infections. Furthermore, a structure–activity relationship analysis indicated that a benzyl substitution on the aniline nitrogen of this compound improved potency while augmenting its drug-like properties. In addition, 5d exhibited antiviral activity against various viruses of Flaviviridae family of worldwide public health importance, such as dengue, Japanese encephalitis and classical swine fever viruses, indicating its potential as a lead compound for generating 1,2,4-oxadiazole derivatives with broad-spectrum anti-flaviviral properties.
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References
Baloch AS, Liu C, Liang X, Liu Y, Chen J, Cao R, Zhou B (2019) Avian flavivirus enters BHK-21 cells by a low pH-dependent endosomal pathway. Viruses 11:1112. https://doi.org/10.3390/v11121112
Baud D, Gubler DJ, Schaub B, Lanteri MC, Musso D (2017) An update on Zika virus infection. Lancet 390:2099–2109. https://doi.org/10.1016/S0140-6736(17)31450-2
Baykov S, Sharonova T, Shetnev A, Rozhkov S, Kalinin S, Smirnov AV (2017) The first one-pot ambient-temperature synthesis of 1,2,4-oxadiazoles from amidoximes and carboxylic acid esters. Tetrahedron 73:945–951. https://doi.org/10.1016/j.tet.2017.01.007
Benmansour F, Eydoux C, Querat G, de Lamballerie X, Canard B, Alvarez K, Guillemot JC, Barral K (2016) Novel 2-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,3,4-oxadiazole and 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole derivatives as dengue virus inhibitors targeting NS5 polymerase. Eur J Med Chem 109:146–156. https://doi.org/10.1016/j.ejmech.2015.12.046
Biernacki K, Daśko M, Ciupak O, Kubiński K, Rachon J, Demkowicz S (2020) Novel 1,2,4-oxadiazole derivatives in drug discovery. Pharmaceuticals 13:111. https://doi.org/10.3390/ph13060111
Broutet N, Krauer F, Riesen M, Khalakdina A, Almiron M, Aldighieri S, Espinal M, Low N, Dye C (2016) Zika virus as a cause of neurologic disorders. N Engl J Med 374:1506–1509. https://doi.org/10.1056/NEJMp1602708
Cao-Lormeau VM, Roche C, Teissier A, Robin E, Berry AL, Mallet HP, Sall AA, Musso D (2014) Zika virus, french polynesia, south pacific, 2013. Emerg Infect Dis 20:1085–1086. https://doi.org/10.3201/eid2006.140138
Carbone M, Li Y, Irace C, Mollo E, Castelluccio F, Di Pascale A, Cimino G, Santamaria R, Guo YW, Gavagnin M (2011) Structure and cytotoxicity of phidianidines A and B: first finding of 1,2,4-oxadiazole system in a marine natural product. Org Lett 13:2516–2519. https://doi.org/10.1021/ol200234r
Carossino M, Li Y, Lee PYA, Tsai CF, Chou PH, Williams D, Skillman A, Cook RF, Brown G, Chang HFG, Wang HTT, Balasuriya UBR (2017) Evaluation of a field-deployable reverse transcription-insulated isothermal PCR for rapid and sensitive on-site detection of Zika virus. BMC Infect Dis 17:778. https://doi.org/10.1186/s12879-017-2852-4
Coluccia A, Puxeddu M, Nalli M, Wei CK, Wu YH, Mastrangelo E, Elamin T, Tarantino D, Bugert JJ, Schreiner B, Nolte J, Schwarze F, La Regina G, Lee JC, Silvestri R (2020) Discovery of Zika virus NS2B/NS3 inhibitors that prevent mice from life-threatening infection and brain damage. ACS Med Chem Lett 11:1869–1874. https://doi.org/10.1021/acsmedchemlett.9b00405
de Souza AAA, Torres LR, Capobianco LRPL, de Paula VS, Cascabulho CM, Salomão K, Bonecini-Almeida MdG, Ferreira MdLG, Boechat N, Pinheiro LCdS, de Souza EM (2020) Chloroquine and sulfadoxine derivatives inhibit ZIKV replication in cervical cells. Viruses 13:36. https://doi.org/10.3390/v13010036
Dick GWA, Kitchen SF, Haddow AJ (1952) Zika virus (I). Isolations and serological specificity. Trans R Soc Trop Med Hyg 46:509–520. https://doi.org/10.1016/0035-9203(52)90042-4
Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, Pretrick M, Marfel M, Holzbauer S, Dubray C, Guillaumot L, Griggs A, Bel M, Lambert AJ, Laven J, Kosoy O, Panella A, Biggerstaff BJ, Fischer M, Hayes EB (2009) Zika virus outbreak on Yap Island, federated states of micronesia. N Engl J Med 360:2536–2543. https://doi.org/10.1056/NEJMoa0805715
Gao Y, Hu JH, Liang XD, Chen J, Liu CC, Liu YY, Cheng Y, Go YY, Zhou B (2021) Curcumin inhibits classical swine fever virus replication by interfering with lipid metabolism. Vet Microbiol 259:109152. https://doi.org/10.1016/j.vetmic.2021.109152
Grard G, Caron M, Mombo IM, Nkoghe D, Ondo SM, Jiolle D, Fontenille D, Paupy C, Leroy EM (2014) Zika virus in Gabon (Central Africa)-2007: a new threat from Aedes albopictus? PLoS Negl Trop Dis 8:e2681. https://doi.org/10.1371/journal.pntd.0002681
Hermit MB, Greenwood JR, Bräuner-Osborne H (2004) Mutation-induced quisqualic acid and ibotenic acid affinity at the metabotropic glutamate receptor subtype 4: ligand selectivity results from a synergy of several amino acid residues. J Biol Chem 279:34811–34817. https://doi.org/10.1074/jbc.M404109200
Kim J, Shin JS, Ahn S, Han SB, Jung YS (2018) 3-Aryl-1,2,4-oxadiazole derivatives active against human rhinovirus. ACS Med Chem Lett 9:667–672. https://doi.org/10.1021/acsmedchemlett.8b00134
Krauer F, Riesen M, Reveiz L, Oladapo OT, Martínez-Vega R, Porgo TV, Haefliger A, Broutet NJ, Low N, W.H.O. Zika Causality Working Group (2017) Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: systematic review. PLoS Med 14:e1002203. https://doi.org/10.1371/journal.pmed.1002203
Kumpan K, Nathubhai A, Zhang C, Wood PJ, Lloyd MD, Thompson AS, Haikarainen T, Lehtiö L, Threadgill MD (2015) Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases. Bioorg Med Chem 23:3013–3032. https://doi.org/10.1016/j.bmc.2015.05.005
Kuno G, Chang GJJ (2007) Full-length sequencing and genomic characterization of bagaza, kedougou, and Zika viruses. Arch Virol 152:687–696. https://doi.org/10.1007/s00705-006-0903-z
Li F, Lee EM, Sun X, Wang D, Tang H, Zhou GC (2020) Design, synthesis and discovery of andrographolide derivatives against Zika virus infection. Eur J Med Chem 187:111925. https://doi.org/10.1016/j.ejmech.2019.111925
Liu CC, Liu YY, Cheng Y, Zhang YN, Zhang J, Liang XD, Gao Y, Chen H, Baloch AS, Yang Q, Go YY, Zhou B (2021) The ESCRT-I subunit Tsg101 plays novel dual roles in entry and replication of classical swine fever virus. J Virol 95:e01928-e2020. https://doi.org/10.1128/JVI.01928-20
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Nie S, Zhao J, Wu X, Yao Y, Wu F, Lin YL, Li X, Kneubehl AR, Vogt MB, Rico-Hesse R, Song Y (2021) Synthesis, structure–activity relationship and antiviral activity of indole-containing inhibitors of flavivirus NS2B-NS3 protease. Eur J Med Chem 225:113767. https://doi.org/10.1016/j.ejmech.2021.113767
Ott GR, Anzalone AV (2011) Synthetic studies toward 3-(acylamino)-1H-indazoles and development of a one-pot, microwave-assisted, oxadiazole condensation/Boulton–Katritzky rearrangement. Synlett 20:3018–3022. https://doi.org/10.1055/s-0031-1289893
Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR (2016) Zika virus and birth defects-reviewing the evidence for causality. N Engl J Med 374:1981–1987. https://doi.org/10.1056/NEJMsr1604338
Rassias G, Zogali V, Swarbrick CMD, Chan KWK, Chan SA, Gwee CP, Wang S, Kaplanai E, Canko A, Kiousis D, Lescar J, Luo D, Matsoukas MT, Vasudevan SG (2019) Cell-active carbazole derivatives as inhibitors of the Zika virus protease. Eur J Med Chem 180:536–545. https://doi.org/10.1016/j.ejmech.2019.07.007
Spizzichino S, Mattedi G, Lauder K, Valle C, Aouadi W, Canard B, Decroly E, Kaptein SJF, Neyts J, Graham C, Sule Z, Barlow DJ, Silvestri R, Castagnolo D (2020) Design, synthesis and discovery of N, N’-carbazoyl-aryl-urea inhibitors of Zika NS5 methyltransferase and virus replication. ChemMedChem 15:385–390. https://doi.org/10.1002/cmdc.201900533
Thibaut HJ, De Palma AM, Neyts J (2012) Combating enterovirus replication: state-of-the-art on antiviral research. Biochem Pharmacol 83:185–192. https://doi.org/10.1016/j.bcp.2011.08.016
Wang Y, Zhou R, Quan Y, Chen S, Shi X, Li Y, Cen S (2020) Design, synthesis, and evaluation of novel 4-amino-2-(4-benzylpiperazin-1-yl)methylbenzonitrile compounds as Zika inhibitors. Bioorg Med Chem Lett 30:126906. https://doi.org/10.1016/j.bmcl.2019.126906
Wei J, Hameed M, Wang X, Zhang J, Guo S, Anwar MN, Pang L, Liu K, Li B, Shao D, Qiu Y, Zhong D, Zhou B, Ma Z (2020) Antiviral activity of phage display-selected peptides against Japanese encephalitis virus infection in vitro and in vivo. Antiviral Res 174:104673. https://doi.org/10.1016/j.antiviral.2019.104673
Acknowledgements
The chemical library used in this study was kindly provided by the Korea Chemical Bank of the Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea. This research was supported by Korea Disease Control and Prevention Agency (Grant Number 2018-ER53001-00) and KRICT intramural funding (Grant Numbers KK1703-E00, KK1803-E00, KK1931-20, SI2132-20 and SI2232-20). In addition, Go, Y. Y. was supported by a start-up fund from the City University of Hong Kong, Hong Kong SAR, China.
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Nam, S., Na, H.G., Oh, E.H. et al. Discovery and synthesis of 1,2,4-oxadiazole derivatives as novel inhibitors of Zika, dengue, Japanese encephalitis, and classical swine fever virus infections. Arch. Pharm. Res. 45, 280–293 (2022). https://doi.org/10.1007/s12272-022-01380-8
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DOI: https://doi.org/10.1007/s12272-022-01380-8