{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:10:49Z","timestamp":1782274249982,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T00:00:00Z","timestamp":1695686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["22-25-00161"],"award-info":[{"award-number":["22-25-00161"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Emerging and re-emerging viruses periodically cause outbreaks and epidemics around the world, which ultimately lead to global events such as the COVID-19 pandemic. Thus, the urgent need for new antiviral drugs is obvious. Over more than a century of antiviral development, nucleoside analogs have proven to be promising agents against diversified DNA and RNA viruses. Here, we present the synthesis and evaluation of the antiviral activity of nucleoside analogs and their deglycosylated derivatives based on a hydroxybenzo[4,5]imidazo[1,2-c]pyrimidin-1(2H)-one scaffold. The antiviral activity was evaluated against a panel of structurally and phylogenetically diverse RNA and DNA viruses. The leader compound showed micromolar activity against representatives of the family Coronaviridae, including SARS-CoV-2, as well as against respiratory syncytial virus in a submicromolar range without noticeable toxicity for the host cells. Surprisingly, methylation of the aromatic hydroxyl group of the leader compound resulted in micromolar activity against the varicella-zoster virus without any significant impact on cell viability. The leader compound was shown to be a weak inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase. It also inhibited biocondensate formation important for SARS-CoV-2 replication. The active compounds may be considered as a good starting point for further structure optimization and mechanistic and preclinical studies.<\/jats:p>","DOI":"10.3390\/ijms241914540","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T03:45:23Z","timestamp":1695699923000},"page":"14540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Phenotypic Test of Benzo[4,5]imidazo[1,2-c]pyrimidinone-Based Nucleoside and Non-Nucleoside Derivatives against DNA and RNA Viruses, Including Coronaviruses"],"prefix":"10.3390","volume":"24","author":[{"given":"Polina","family":"Kamzeeva","sequence":"first","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Petushkov","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics, National Research Centre \u2018Kurchatov Institute\u2019, 123182 Moscow, Russia"},{"name":"Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Knizhnik","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"},{"name":"Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Snoeck","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Khodarovich","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Ryabukhina","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8961-5890","authenticated-orcid":false,"given":"Vera","family":"Alferova","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Eshtukov-Shcheglov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeny","family":"Belyaev","sequence":"additional","affiliation":[{"name":"Frumkin Institute of Physical Chemistry and Electrochemistry, RAS, 119071 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Svetlova","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7356-397X","authenticated-orcid":false,"given":"Tatiana","family":"Vedekhina","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey","family":"Kulbachinskiy","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics, National Research Centre \u2018Kurchatov Institute\u2019, 123182 Moscow, Russia"},{"name":"Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Varizhuk","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"},{"name":"Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2609-4896","authenticated-orcid":false,"given":"Graciela","family":"Andrei","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3268-2352","authenticated-orcid":false,"given":"Andrey","family":"Aralov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chowell, G., Echevarr\u00eda-Zuno, S., Viboud, C., Simonsen, L., Tamerius, J., Miller, M.A., and Borja-Aburto, V.H. (2011). Characterizing the Epidemiology of the 2009 Influenza A\/H1N1 Pandemic in Mexico. PLoS Med., 8.","DOI":"10.1371\/journal.pmed.1000436"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cenciarelli, O., Pietropaoli, S., Malizia, A., Carestia, M., D\u2019Amico, F., Sassolini, A., Di Giovanni, D., Rea, S., Gabbarini, V., and Tamburrini, A. (2015). Ebola Virus Disease 2013-2014 Outbreak in West Africa: An Analysis of the Epidemic Spread and Response. Int. J. Microbiol., 2015.","DOI":"10.1155\/2015\/769121"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/s12985-015-0439-5","article-title":"MERS Coronavirus: Diagnostics, Epidemiology and Transmission","volume":"12","author":"Mackay","year":"2015","journal-title":"Virol. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nrmicro2655","article-title":"Viral Subversion of the Host Protein Synthesis Machinery","volume":"9","author":"Walsh","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.tim.2018.04.004","article-title":"Drug Repurposing for Viral Infectious Diseases: How Far Are We?","volume":"26","author":"Mercorelli","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hadj Hassine, I., Ben M\u2019hadheb, M., and Men\u00e9ndez-Arias, L. (2022). Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity. Viruses, 14.","DOI":"10.3390\/v14040841"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"409","DOI":"10.2533\/chimia.2022.409","article-title":"Comparison of the Old and New\u2014Novel Mechanisms of Action for Anti-Coronavirus Nucleoside Analogues","volume":"76","author":"Thames","year":"2022","journal-title":"Chimia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1134\/S0026893321040105","article-title":"Antiviral and Antimicrobial Nucleoside Derivatives: Structural Features and Mechanisms of Action","volume":"55","author":"Zenchenko","year":"2021","journal-title":"Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ramdhan, P., and Li, C. (2022). Targeting Viral Methyltransferases: An Approach to Antiviral Treatment for SsRNA Viruses. Viruses, 14.","DOI":"10.3390\/v14020379"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Takizawa, N., Takada, H., Umekita, M., Igarashi, M., and Takahashi, Y. (2022). Anti-Influenza Virus Activity of Methylthio-Formycin Distinct From That of T-705. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.802671"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Geraghty, R., Aliota, M., and Bonnac, L. (2021). Broad-Spectrum Antiviral Strategies and Nucleoside Analogues. Viruses, 13.","DOI":"10.3390\/v13040667"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nrd4010","article-title":"Advances in the Development of Nucleoside and Nucleotide Analogues for Cancer and Viral Diseases","volume":"12","author":"Jordheim","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/978-3-540-79086-0_11","article-title":"Antiviral Resistance and Impact on Viral Replication Capacity: Evolution of Viruses Under Antiviral Pressure Occurs in Three Phases","volume":"Volume 189","author":"Bartenschlager","year":"2009","journal-title":"Antiviral Strategies"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.antiviral.2018.04.004","article-title":"The Evolution of Nucleoside Analogue Antivirals: A Review for Chemists and Non-Chemists. Part 1: Early Structural Modifications to the Nucleoside Scaffold","volume":"154","author":"Yates","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.antiviral.2018.11.016","article-title":"The Evolution of Antiviral Nucleoside Analogues: A Review for Chemists and Non-Chemists. Part II: Complex Modifications to the Nucleoside Scaffold","volume":"162","author":"Yates","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1016\/j.bmcl.2012.02.105","article-title":"Synthesis and Antiviral Activity of a Series of 1\u2032-Substituted 4-Aza-7,9-Dideazaadenosine C-Nucleosides","volume":"22","author":"Cho","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3385","DOI":"10.1016\/j.bmcl.2013.03.077","article-title":"Synthesis and Evaluation of Janus Type Nucleosides as Potential HCV NS5B Polymerase Inhibitors","volume":"23","author":"Zhou","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1007\/s10593-020-02713-5","article-title":"Nucleoside Analogs with Fleximer Nucleobase","volume":"56","author":"Chudinov","year":"2020","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Thames, J.E., Waters, C.D., Valle, C., Bassetto, M., Aouadi, W., Martin, B., Selisko, B., Falat, A., Coutard, B., and Brancale, A. (2020). Synthesis and Biological Evaluation of Novel Flexible Nucleoside Analogues That Inhibit Flavivirus Replication in Vitro. Bioorg. Med. Chem., 28.","DOI":"10.1016\/j.bmc.2020.115713"},{"key":"ref_20","first-page":"19","article-title":"Base-Modified Nucleosides: Etheno Derivatives","volume":"4","author":"Framski","year":"2016","journal-title":"Front. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.ejmech.2014.12.026","article-title":"Bioactive Fused Heterocycles: Nucleoside Analogs with an Additional Ring","volume":"97","author":"Framski","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.antiviral.2019.01.010","article-title":"Antiviral Activity Spectrum of Phenoxazine Nucleoside Derivatives","volume":"163","author":"Kozlovskaya","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1016\/j.bmcl.2003.08.028","article-title":"Novel Bicyclic Furanopyrimidines with Dual Anti-VZV and -HCMV Activity","volume":"13","author":"McGuigan","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4993","DOI":"10.1021\/jm000210m","article-title":"Highly Potent and Selective Inhibition of Varicella-Zoster Virus by Bicyclic Furopyrimidine Nucleosides Bearing an Aryl Side Chain","volume":"43","author":"McGuigan","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"De Clercq, E. (2022). FV-100 for the Treatment of Varicella-Virus (VZV) Infections: Quo Vadis?. Viruses, 14.","DOI":"10.3390\/v14040770"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Matyugina, E., Petushkov, I., Surzhikov, S., Kezin, V., Maslova, A., Ivanova, O., Smirnova, O., Kirillov, I., Fedyakina, I., and Kulbachinskiy, A. (2023). Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043361"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Svetlova, J., Knizhnik, E., Manuvera, V., Severov, V., Shirokov, D., Grafskaia, E., Bobrovsky, P., Matyugina, E., Khandazhinskaya, A., and Kozlovskaya, L. (2022). Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315281"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cascarina, S.M., and Ross, E.D. (2022). Phase Separation by the SARS-CoV-2 Nucleocapsid Protein: Consensus and Open Questions. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101677"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1162211","DOI":"10.3389\/fimmu.2023.1162211","article-title":"Molecular Mechanisms and Cellular Functions of Liquid-Liquid Phase Separation during Antiviral Immune Responses","volume":"14","author":"Yang","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"985622","DOI":"10.3389\/fimmu.2022.985622","article-title":"When Liquid-Liquid Phase Separation Meets Viral Infections","volume":"13","author":"Wei","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrm.2017.7","article-title":"Biomolecular Condensates: Organizers of Cellular Biochemistry","volume":"18","author":"Banani","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12977-023-00619-6","article-title":"Biomolecular Condensates: Insights into Early and Late Steps of the HIV-1 Replication Cycle","volume":"20","author":"Uversky","year":"2023","journal-title":"Retrovirology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1134\/S1068162023050229","article-title":"Condensates of SARS-CoV-2 Nucleoprotein on Viral RNA and Their Small Molecule Modulators (A Review)","volume":"49","author":"Svetlova","year":"2023","journal-title":"Russ. J. Bioorganic Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bbrc.2021.01.018","article-title":"ATP Biphasically Modulates LLPS of SARS-CoV-2 Nucleocapsid Protein and Specifically Binds Its RNA-Binding Domain","volume":"541","author":"Dang","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1038\/s41467-021-22297-8","article-title":"GCG Inhibits SARS-CoV-2 Replication by Disrupting the Liquid Phase Condensation of Its Nucleocapsid Protein","volume":"12","author":"Zhao","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1007\/s13238-021-00832-z","article-title":"Understanding the Phase Separation Characteristics of Nucleocapsid Protein Provides a New Therapeutic Opportunity against SARS-CoV-2","volume":"12","author":"Zhao","year":"2021","journal-title":"Protein Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1021\/tx00048a007","article-title":"Large Scale Synthesis of P-Benzoquinone-2\u2032-Deoxycytidine and p-Benzoquinone-2\u2032-Deoxyadenosine Adducts and Their Site-Specific Incorporation into DNA Oligodeoxyribonucleotides","volume":"8","author":"Chenna","year":"1995","journal-title":"Chem. Res. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.antiviral.2013.01.011","article-title":"3\u2032,5\u2032Di-O-Trityluridine Inhibits in Vitro Flavivirus Replication","volume":"98","author":"Selisko","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/open.201500216","article-title":"Anti-Flavivirus Activity of Different Tritylated Pyrimidine and Purine Nucleoside Analogues","volume":"5","author":"McGuigan","year":"2016","journal-title":"ChemistryOpen"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3389\/fgene.2017.00125","article-title":"Origin and Evolution of RNA-Dependent RNA Polymerase","volume":"8","year":"2017","journal-title":"Front. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/febs.16587","article-title":"Effects of Natural RNA Modifications on the Activity of SARS-CoV-2 RNA-dependent RNA Polymerase","volume":"290","author":"Petushkov","year":"2023","journal-title":"FEBS J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6041","DOI":"10.1038\/s41467-020-19843-1","article-title":"Nucleocapsid Protein of SARS-CoV-2 Phase Separates into RNA-Rich Polymerase-Containing Condensates","volume":"11","author":"Savastano","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8168","DOI":"10.1093\/nar\/gkac596","article-title":"Double-Stranded RNA Drives SARS-CoV-2 Nucleocapsid Protein to Undergo Phase Separation at Specific Temperatures","volume":"50","author":"Roden","year":"2022","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14540\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:58:24Z","timestamp":1760129904000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,26]]},"references-count":43,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms241914540"],"URL":"https:\/\/doi.org\/10.3390\/ijms241914540","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,26]]}}}