{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:12:06Z","timestamp":1760238726980,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,22]],"date-time":"2020-08-22T00:00:00Z","timestamp":1598054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology Taiwan","award":["106-2113-M-007-011-MY2 and 107-3017-F-007-002"],"award-info":[{"award-number":["106-2113-M-007-011-MY2 and 107-3017-F-007-002"]}]},{"name":"Ministry of Education Taiwan","award":["106N501CE1 and 107QR001I5"],"award-info":[{"award-number":["106N501CE1 and 107QR001I5"]}]},{"name":"European Commission SILVER project within the 7th Framework Programme as Cooperation Project Grant Agreement","award":["103G603-14 and 260644"],"award-info":[{"award-number":["103G603-14 and 260644"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The modern world has no available drugs for the treatment of enteroviruses (EV), which affect millions of people worldwide each year. The EV71 is a major causative disease for hand, foot, and mouth disease; sometimes it is associated with severe central nervous system diseases. Treatment for enteroviral infection is mainly supportive; treatment for aseptic meningitis caused by enteroviruses is also generally symptomatic. Upon the urgent request of new anti-enterovirus drugs, a series of hinged aromatic compounds with polynulei were synthesized through two different chemical pathways. Among these morpholine\u2013furan\/thiophene\/pyrrole\u2013benzene\u2013pyrazole conjugates, three new agents exhibited inhibitory activity with EC50 = 2.29\u20136.16 \u03bcM toward EV71 strain BrCr in RD cells. Their selectivity index values were reached as high as 33.4. Their structure\u2013activity relationship was deduced that a thiophene derivative with morpholine and trifluorobenzene rings showed the greatest antiviral activity, with EC50 = 2.29 \u03bcM.<\/jats:p>","DOI":"10.3390\/molecules25173821","type":"journal-article","created":{"date-parts":[[2020,8,23]],"date-time":"2020-08-23T22:10:14Z","timestamp":1598220614000},"page":"3821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei"],"prefix":"10.3390","volume":"25","author":[{"given":"Jih Ru","family":"Hwu","sequence":"first","affiliation":[{"name":"Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan"},{"name":"Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 300, Taiwan"},{"name":"Department of Chemistry, National Central University, Jhongli City, Taoyuan 320, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1336-8547","authenticated-orcid":false,"given":"Avijit","family":"Panja","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srinivasan","family":"Jayakumar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0585-3419","authenticated-orcid":false,"given":"Shwu-Chen","family":"Tsay","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan"},{"name":"Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 300, Taiwan"},{"name":"Department of Chemistry, National Central University, Jhongli City, Taoyuan 320, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kui-Thong","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan"},{"name":"Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 300, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Chieh","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan"},{"name":"Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 300, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Chen","family":"Hu","sequence":"additional","affiliation":[{"name":"Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 300, Taiwan"},{"name":"Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pieter","family":"Leyssen","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johan","family":"Neyts","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,22]]},"reference":[{"key":"ref_1","unstructured":"Merck &, Co (2019, July 17). Overview of Enterovirus Infections, Available online: https:\/\/www.msdmanuals.com\/professional\/infectious-diseases\/enteroviruses\/overview-of-enterovirus-infections."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1128\/JCM.39.4.1299-1302.2001","article-title":"Type-specific detection of echovirus 30 isolates using degenerate reverse transcriptase PCR primers","volume":"39","author":"Kilpatrick","year":"2011","journal-title":"J. Clin. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1086\/343809","article-title":"Lactoferrin inhibits enterovirus 71 infection of human embryonal rhabdomyosarcoma cells in vitro","volume":"186","author":"Lin","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_4","unstructured":"Schwartz, R.A. (2019, August 23). Enteroviruses Treatment & Management. Medscape, Available online: https:\/\/emedicine.medscape.com\/article\/217146-treatment."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1021\/acsinfecdis.9b00070","article-title":"Efficient blocking of enterovirus 71 infection by heparan sulfate analogues acting as decoy receptors","volume":"5","author":"Earley","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jmii.2013.11.011","article-title":"Development of antiviral agents toward enterovirus 71 infection","volume":"48","author":"Pourianfar","year":"2015","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1021\/acsmedchemlett.8b00134","article-title":"3-Aryl-1,2,4-oxadiazole derivatives active against human rhinovirus","volume":"9","author":"Kim","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1021\/acsmedchemlett.7b00188","article-title":"Discovery of potent EV71 capsid inhibitors for treatment of HFMD","volume":"8","author":"Li","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5472","DOI":"10.1021\/acs.jmedchem.7b00175","article-title":"A Novel series of highly potent small molecule inhibitors of rhinovirus replication","volume":"60","author":"Kim","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ejmech.2016.01.036","article-title":"Modification of the length and structure of the linker of N6-benzyladenosine modulates its selective antiviral activity against enterovirus 71","volume":"111","author":"Drenichev","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1016\/j.bmc.2016.05.055","article-title":"Discovery of 3-benzyl-1,3-benzoxazine-2,4-dione analogues as allosteric mitogen-activated kinase kinase (MEK) inhibitors and anti-enterovirus 71 (EV71) agents","volume":"24","author":"Sun","year":"2016","journal-title":"Biorg. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4056","DOI":"10.1021\/acs.jmedchem.9b00091","article-title":"Discovery, optimization, and target identification of novel potent broad-spectrum antiviral inhibitors","volume":"62","author":"Yang","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1021\/acs.jmedchem.5b01803","article-title":"Identification and structure\u2013activity relationships of diarylhydrazides as novel potent and selective human enterovirus inhibitors","volume":"59","author":"Han","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.antiviral.2016.04.003","article-title":"Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds","volume":"13","author":"Smee","year":"2016","journal-title":"Antiviral Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.ejmech.2014.11.048","article-title":"Chemical modification of the plant isoprenoid cytokinin N6-isopentenyladenosine yields a selective inhibitor of human enterovirus 71 replication","volume":"90","author":"Tararov","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1016\/j.bmcl.2016.02.039","article-title":"Synthesis and structure\u2013activity relationship of \u03b1-keto amides as enterovirus 71 3C protease inhibitors","volume":"26","author":"Zeng","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4562","DOI":"10.1021\/acs.jmedchem.9b01828","article-title":"\u03b1-Ketoamides as broad spectrum inhibitors of coronavirus and enterovirus replication: Structure-based design, synthesis, and activity assessment","volume":"63","author":"Zhang","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.bioorg.2019.02.020","article-title":"Anti-enteroviral activity of new MDL-860 analogues: Synthesis, in vitro\/in vivo studies and QSAR analysis","volume":"85","author":"Nikolova","year":"2019","journal-title":"Bioorg.Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.ejmech.2016.08.064","article-title":"Structure\u2013activity relationship study of peptidomimetic aldehydes as enterovirus 71 3C protease inhibitors","volume":"124","author":"Zhai","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4074","DOI":"10.1021\/acs.jmedchem.9b00115","article-title":"Discovery of quinoline analogues as potent antivirals against enterovirus D68 (EV-D68)","volume":"62","author":"Musharrafieh","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jep.2019.02.045","article-title":"Antiviral activity of sophoridine against enterovirus 71 in vitro","volume":"236","author":"Ren","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Segun, P.A., Ogbole, O.O., Akinleye, T.E., Faleye, T.O.C., and Adeniji, A.J. (2019). In vitro anti-enteroviral activity of stilbenoids isolated from the leaves of Macaranga barteri. Nat. Prod. Res., 1\u20135.","DOI":"10.1080\/14786419.2019.1644505"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1021\/acs.jmedchem.9b01737","article-title":"Scaffold simplification strategy leads to a novel generation of dual human immunodeficiency virus and enterovirus-A71 entry inhibitors","volume":"63","author":"Sun","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.ejmech.2016.10.019","article-title":"Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening","volume":"124","author":"Ma","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.antiviral.2012.12.005","article-title":"Antiviral drug discovery for the treatment of enterovirus 71 infections","volume":"97","author":"Shang","year":"2013","journal-title":"Antiviral Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"112007","DOI":"10.1016\/j.ejmech.2019.112007","article-title":"Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses","volume":"188","author":"Egorova","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.ejmech.2019.04.048","article-title":"Design, synthesis and pharmacological evaluation of a novel mTOR-targeted anti-EV71 agent","volume":"175","author":"Hao","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1021\/acs.jmedchem.7b01863","article-title":"Synthesis and Structure\u2013activity relationship (SAR) studies of novel pyrazolopyridine derivatives as inhibitors of enterovirus replication","volume":"61","author":"Xing","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.ejmech.2019.06.008","article-title":"Back to the future: Advances in development of broad-spectrum capsid-binding inhibitors of enteroviruses","volume":"178","author":"Egorova","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.antiviral.2014.03.010","article-title":"Substituted 2,6-bis(benzimidazol-2-yl)pyridines: A novel chemical class of pestivirus inhibitors that targets a hot spot for inhibition of pestivirus replication in the RNA-dependent RNA polymerase","volume":"106","author":"Musiu","year":"2014","journal-title":"Antiviral Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.ejmech.2013.03.054","article-title":"3-Biphenylimidazo[1,2-a]pyridines or [1,2-b]pyridazines and analogues, novel flaviviridae inhibitors","volume":"64","author":"Musiu","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.ejmech.2013.02.008","article-title":"Coumarins hinged directly on benzimidazoles and their ribofuranosides to inhibit hepatitis C virus","volume":"63","author":"Tsay","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1128\/AAC.00934-08","article-title":"Mutations in the nonstructural protein 3A confer resistance to the novel enterovirus replication inhibitor TTP-8307","volume":"53","author":"Thibaut","year":"2009","journal-title":"Antimicrob. Agents. Chemother."},{"key":"ref_34","first-page":"7","article-title":"Medicinal significance of furan derivatives: A review","volume":"2","author":"Banerjee","year":"2012","journal-title":"Int. J. Rev. Life. Sci."},{"key":"ref_35","first-page":"2676","article-title":"Pharmacological action and sar of thiophene derivatives: A review","volume":"5","author":"Kamboj","year":"2012","journal-title":"J. Pharm. Res."},{"key":"ref_36","first-page":"17","article-title":"Recent synthetic and medicinal perspectives of pyrroles: An overview","volume":"1","author":"Kaur","year":"2017","journal-title":"J. Pharm. Chem. Chem. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ejmech.2016.05.043","article-title":"Synthetic strategy and antiviral evaluation of diamide containing heterocycles targeting dengue and yellow fever virus","volume":"121","author":"Saudi","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Karrouchi, K., Radi, S., Ramli, Y., Taoufik, J., Mabkhot, N.Y., Al-aizari, A.F., and Ansar, M.H. (2018). Synthesis and pharmacological activities of pyrazole derivatives: A review. Molecules, 23.","DOI":"10.3390\/molecules23010134"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5891","DOI":"10.1016\/j.bmc.2017.09.035","article-title":"Recently reported biological activities of pyrazole compounds","volume":"25","author":"Faria","year":"2017","journal-title":"Biorg. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1039\/C6NJ03181A","article-title":"Review: Biologically active pyrazole derivatives","volume":"4","author":"Ansari","year":"2017","journal-title":"New. J. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6384","DOI":"10.1016\/j.bmc.2012.08.062","article-title":"Small-molecular inhibitors of Ca2+-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene","volume":"20","author":"Murasawa","year":"2012","journal-title":"Biorg. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5381","DOI":"10.1021\/jo0268409","article-title":"A Novel One-Pot Method for the Preparation of pyrazoles by 1,3-dipolar cycloadditions of diazo compounds generated in situ","volume":"68","author":"Aggarwal","year":"2003","journal-title":"J. Org. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5272","DOI":"10.1021\/jo00225a055","article-title":"Arylation of aromatic heterocycles with arenes and palladium(II) acetate","volume":"50","author":"Itahara","year":"1985","journal-title":"J. Org. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7163","DOI":"10.1002\/ejoc.201101102","article-title":"Methyl 2-Furoate: An alternative reagent to furan for palladium-catalysed direct arylation","volume":"2011","author":"Fu","year":"2011","journal-title":"Eur. J. Org. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9865","DOI":"10.1039\/C9SC03169C","article-title":"Palladium-catalyzed decarbonylative Suzuki\u2013Miyaura cross-coupling of amides by carbon\u2013nitrogen bond activation","volume":"10","author":"Zhou","year":"2019","journal-title":"Chem.Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1021\/jm030767c","article-title":"Determination of conformer-specific partition coefficients in octanol\/water systems","volume":"46","author":"Kraszni","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.ejmech.2014.09.062","article-title":"Synthesis and evaluation of imidazole-4,5- and pyrazine-2,3-dicarboxamides targeting dengue and yellow fever","volume":"87","author":"Saudi","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1021\/cc9800071","article-title":"A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases","volume":"1","author":"Ghose","year":"1999","journal-title":"J. Comb. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/17\/3821\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:05:11Z","timestamp":1760177111000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/17\/3821"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,22]]},"references-count":48,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["molecules25173821"],"URL":"https:\/\/doi.org\/10.3390\/molecules25173821","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2020,8,22]]}}}