{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:00:28Z","timestamp":1782450028658,"version":"3.54.5"},"reference-count":40,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T00:00:00Z","timestamp":1662336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health of Russia","award":["121111200070-4 (P16)"],"award-info":[{"award-number":["121111200070-4 (P16)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite the widespread use of the COVID-19 vaccines, the search for effective antiviral drugs for the treatment of patients infected with SARS-CoV-2 is still relevant. Genetic variability leads to the continued circulation of new variants of concern (VOC). There is a significant decrease in the effectiveness of antibody-based therapy, which raises concerns about the development of new antiviral drugs with a high spectrum of activity against VOCs. We synthesized new analogs of uracil derivatives where uracil was substituted at the N1 and N3 positions. Antiviral activity was studied in Vero E6 cells against VOC, including currently widely circulating SARS-CoV-2 Omicron. All synthesized compounds of the panel showed a wide antiviral effect. In addition, we determined that these compounds inhibit the activity of recombinant SARS-CoV-2 RdRp. Our study suggests that these non-nucleoside uracil-based analogs may be of future use as a treatment for patients infected with circulating SARS-CoV-2 variants.<\/jats:p>","DOI":"10.3390\/ijms231710171","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T05:17:23Z","timestamp":1662441443000},"page":"10171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Antiviral Activity of N1,N3-Disubstituted Uracil Derivatives against SARS-CoV-2 Variants of Concern"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7576-2059","authenticated-orcid":false,"given":"Andrei E.","family":"Siniavin","sequence":"first","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"},{"name":"Department of Molecular Neuroimmune Signalling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail S.","family":"Novikov","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, 400131 Volgograd, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9397-3762","authenticated-orcid":false,"given":"Vladimir A.","family":"Gushchin","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"},{"name":"Department of Virology, Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Terechov","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor A.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"},{"name":"Department of Molecular Neuroimmune Signalling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria P.","family":"Paramonova","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, 400131 Volgograd, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1228-447X","authenticated-orcid":false,"given":"Elena S.","family":"Gureeva","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, 400131 Volgograd, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid I.","family":"Russu","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7399-7628","authenticated-orcid":false,"given":"Nadezhda A.","family":"Kuznetsova","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena V.","family":"Shidlovskaya","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6155-2066","authenticated-orcid":false,"given":"Sergei I.","family":"Luyksaar","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1965-0700","authenticated-orcid":false,"given":"Daria V.","family":"Vasina","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1852-7615","authenticated-orcid":false,"given":"Sergei A.","family":"Zolotov","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nailya A.","family":"Zigangirova","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis Y.","family":"Logunov","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander L.","family":"Gintsburg","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"},{"name":"Department of Infectiology and Virology, Federal State Autonomous Educational Institution of Higher Education I M Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1071\/PY21096","article-title":"Implications of the ongoing coronavirus disease 2019 pandemic for primary care","volume":"28","author":"Shankar","year":"2022","journal-title":"Aust. J. Prim. Health"},{"key":"ref_2","first-page":"155","article-title":"Coronavirus biology and replication: Implications for SARS-CoV-2","volume":"19","author":"Kratzel","year":"2020","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nrmicro775","article-title":"SARS\u2014Beginning to understand a new virus","volume":"1","author":"Stadler","year":"2003","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yadav, R., Chaudhary, J., Jain, N., Chaudhary, P., Khanra, S., Dhamija, P., Sharma, A., Kumar, A., and Handu, S. (2021). Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19. Cells, 10.","DOI":"10.3390\/cells10040821"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/s41579-022-00722-z","article-title":"Antigenic evolution will lead to new SARS-CoV-2 variants with unpredictable severity","volume":"20","author":"Markov","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"671263","DOI":"10.3389\/fmolb.2021.671263","article-title":"Current Strategies of Antiviral Drug Discovery for COVID-19","volume":"8","author":"Mei","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1056\/NEJMoa2116846","article-title":"Early Remdesivir to Prevent Progression to Severe COVID-19 in Outpatients","volume":"386","author":"Gottlieb","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJMoa2116044","article-title":"Molnupiravir for Oral Treatment of COVID-19 in Nonhospitalized Patients","volume":"386","author":"Musungaie","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1056\/NEJMoa2118542","article-title":"Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19","volume":"386","author":"Hammond","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"18567","DOI":"10.7448\/IAS.16.1.18567","article-title":"Non-nucleoside reverse transcriptase inhibitors: A review on pharmacokinetics, pharmacodynamics, safety and tolerability","volume":"16","author":"Usach","year":"2013","journal-title":"J. Int. AIDS Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113201","DOI":"10.1016\/j.ejmech.2021.113201","article-title":"RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic","volume":"213","author":"Tian","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"267","DOI":"10.3389\/fphar.2021.634047","article-title":"Discovering Potential RNA Dependent RNA Polymerase Inhibitors as Prospective Drugs Against COVID-19: An in Silico Approach","volume":"12","author":"Saha","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41422-020-0282-0","article-title":"Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro","volume":"30","author":"Wang","year":"2020","journal-title":"Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41467-019-13940-6","article-title":"Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV","volume":"11","author":"Sheahan","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.virusres.2007.12.015","article-title":"Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase","volume":"134","year":"2008","journal-title":"Virus Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e341","DOI":"10.1016\/S2352-3018(17)30065-6","article-title":"Nucleoside Reverse-Transcriptase Inhibitor Cross-Resistance and Outcomes from Second-Line Antiretroviral Therapy in the Public Health Approach: An Observational Analysis within the Randomised, Open-Label, EARNEST Trial","volume":"4","author":"Paton","year":"2017","journal-title":"Lancet HIV"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.mencom.2020.09.016","article-title":"New acetamide derivatives containing (\u03c9-p-bromophenoxyalkyl)uracil moiety and their anticytomegalovirus activity","volume":"30","author":"Paramonova","year":"2020","journal-title":"Mendeleev Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7035","DOI":"10.1016\/j.bmc.2015.09.033","article-title":"Toward the discovery of dual HCMV\u2013VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides","volume":"23","author":"Babkov","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5794","DOI":"10.1016\/j.bmc.2011.08.025","article-title":"1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents","volume":"19","author":"Novikov","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29487","DOI":"10.1038\/srep29487","article-title":"Exploration of acetanilide derivatives of 1-(\u03c9-phenoxyalkyl)uracils as novel inhibitors of Hepatitis C Virus replication","volume":"6","author":"Magri","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"26014","DOI":"10.1039\/C9RA06313G","article-title":"Ramified derivatives of 5-(perylen-3-ylethynyl)uracil-1-acetic acid and their antiviral properties","volume":"9","author":"Sapozhnikova","year":"2019","journal-title":"RSC Adv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1021\/jm00297a029","article-title":"Irreversible Enzyme Inhibitors. CLXXI. Inhibition of FUDR Phosphorylase from Walker 256 Rat Tumor by 5-Substituted Uracils","volume":"13","author":"Baker","year":"1970","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1016\/j.tet.2005.02.047","article-title":"Regioselective synthesis of 1-allyl- and 1-arylmethyl uracil and thymine derivatives","volume":"61","author":"Malik","year":"2005","journal-title":"Tetrahedron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4151","DOI":"10.1016\/j.bmc.2013.05.009","article-title":"Synthesis and anti-HCMV activity of 1-[\u03c9-(phenoxy)alkyl]uracil derivatives and analogues thereof","volume":"21","author":"Novikov","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.mencom.2019.11.010","article-title":"Synthesis of uracil\u2013coumarin conjugates as potential inhibitors of virus replication","volume":"29","author":"Paramonova","year":"2019","journal-title":"Mendeleev Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s11094-013-0980-8","article-title":"Synthesis and Anti-HIV-1 Activity of 1-[\u03c9-(Phenoxy)Alkyl and -Alkenyl]Uracil Derivatives","volume":"47","author":"Paramonova","year":"2013","journal-title":"Pharm. Chem. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.apsb.2020.04.006","article-title":"D3Targets-2019-nCoV: A webserver for predicting drug targets and for multi-target and multi-site based virtual screening against COVID-19","volume":"10","author":"Shi","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1056\/NEJMoa2007016","article-title":"Compassionate Use of Remdesivir for Patients with Severe COVID-19","volume":"382","author":"Grein","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e02428-20","DOI":"10.1128\/AAC.02428-20","article-title":"Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2","volume":"65","author":"Painter","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1126\/science.abl4784","article-title":"An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19","volume":"374","author":"Owen","year":"2021","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7777","DOI":"10.1007\/s00018-021-03985-6","article-title":"Snake venom phospholipase A2s exhibit strong virucidal activity against SARS-CoV-2 and inhibit the viral spike glycoprotein interaction with ACE2","volume":"78","author":"Siniavin","year":"2021","journal-title":"Experientia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1038\/s41564-020-00802-x","article-title":"Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters","volume":"5","author":"Yuan","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shidlovskaya, E.V., Kuznetsova, N.A., Divisenko, E.V., Nikiforova, M.A., Siniavin, A.E., Ogarkova, D.A., Shagaev, A.V., Semashko, M.A., Tkachuk, A.P., and Burgasova, O.A. (2021). The Value of Rapid Antigen Tests for Identifying Carriers of Viable SARS-CoV-2. Viruses, 13.","DOI":"10.1101\/2021.03.10.21252667"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1021\/ci300604z","article-title":"Lessons Learned in Empirical Scoring with smina from the CSAR 2011 Benchmarking Exercise","volume":"53","author":"Koes","year":"2013","journal-title":"J. Chem. Inf. Model."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1016\/j.cell.2021.05.033","article-title":"Coupling of N7-methyltransferase and 3\u2032-5\u2032 exoribonuclease with SARS-CoV-2 polymerase reveals mechanisms for capping and proofreading","volume":"184","author":"Yan","year":"2021","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"W665","DOI":"10.1093\/nar\/gkh381","article-title":"PDB2PQR: An automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations","volume":"32","author":"Dolinsky","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"W522","DOI":"10.1093\/nar\/gkm276","article-title":"PDB2PQR: Expanding and upgrading automated preparation of biomolecular structures for molecular simulations","volume":"35","author":"Dolinsky","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_40","unstructured":"(2022, June 18). PyMOL. Available online: https:\/\/www.pymol.org\/pymol.html?."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/10171\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:23:32Z","timestamp":1760142212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/10171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,5]]},"references-count":40,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231710171"],"URL":"https:\/\/doi.org\/10.3390\/ijms231710171","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,5]]}}}