{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:10:09Z","timestamp":1789135809253,"version":"build-2803163510"},"reference-count":48,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza Universit? di Roma","doi-asserted-by":"publisher","award":["RG124190BB0EB5C9"],"award-info":[{"award-number":["RG124190BB0EB5C9"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit? e della Ricerca","doi-asserted-by":"publisher","award":["20228NPP2Y"],"award-info":[{"award-number":["20228NPP2Y"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit? e della Ricerca","doi-asserted-by":"publisher","award":["PE00000007"],"award-info":[{"award-number":["PE00000007"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still a major public health issue, even today. Among the SARS-CoV-2 nonstructural proteins, the main protease (Mpro) plays a critical role in viral polyprotein processing and is therefore indispensable for viral replication. For this reason, it represents one of the most promising therapeutic targets for the development of antiviral agents against SARS-CoV-2. Currently, only one protease antiviral agent (nirmatrelvir) has received emergency approval for COVID-19 treatment, the disease caused by SARS-CoV-2 infection. However, the emergence of viral mutations may compromise its efficacy, highlighting the urgent need to develop new, safe, and effective protease antiviral agents. In the present work, we designed and synthesized new SARS-CoV-2 Mpro small-molecule inhibitors endowed with a pyrimidine scaffold. A series of derivatives were evaluated in both biochemical and cell-based assays to assess their antiviral efficacy, with some of them being able to inhibit the SARS-CoV-2 Mpro activity and to suppress viral replication. Docking studies were confirmed by site-directed mutagenesis, and the mechanism of action of the most promising compound was elucidated.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00583","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:01:32Z","timestamp":1786122092000},"page":"3253-3264","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the\nPyrimidine Scaffold for the Development\nof SARS-CoV-2 M\n                    <b>pro<\/b>\n                    Inhibitors"],"prefix":"10.1021","volume":"12","author":[{"given":"Salvatore","family":"Nieddu","sequence":"first","affiliation":[{"name":"University of Cagliari , , , ,","place":["Cagliari, Monserrato, Italy, SS-554"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3911-6833","authenticated-orcid":true,"given":"Giuseppe","family":"Ruggieri","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universita\u0300 di Roma , , P. le Aldo Moro 5 , ,","place":["Rome, Italy, I-00185"]},{"name":"University of Pavia , , ,","place":["Pavia, Italy, 27100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"De Santis","sequence":"additional","affiliation":[{"name":"Defence Institute for Biomedical Sciences , via di Villa Fonseca 6 , ,","place":["Rome, Italy, 00184"]},{"name":"\u201cSapienza\u201d Universita\u0300 di Roma , , p.Le Aldo Moro, 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Malune","sequence":"additional","affiliation":[{"name":"University of Cagliari , , , ,","place":["Cagliari, Monserrato, Italy, SS-554"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4531-3612","authenticated-orcid":true,"given":"Elisa","family":"Patacchini","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universita\u0300 di Roma , , P. le Aldo Moro 5 , ,","place":["Rome, Italy, I-00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5724-612X","authenticated-orcid":true,"given":"Valentina Noemi","family":"Madia","sequence":"additional","affiliation":[{"name":"Roma Tre University , , Viale Guglielmo Marconi 446 , ,","place":["Rome, Italy, 00146"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-5503","authenticated-orcid":true,"given":"Francesco","family":"Saccoliti","sequence":"additional","affiliation":[{"name":"Link Campus University , , via Del Casale di San Pio V 44 , ,","place":["Rome, Italy, I-00165"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0158-5816","authenticated-orcid":true,"given":"Antonella","family":"Messore","sequence":"additional","affiliation":[{"name":"Link Campus University , , via Del Casale di San Pio V 44 , ,","place":["Rome, Italy, I-00165"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3724-4133","authenticated-orcid":true,"given":"Laura","family":"Zarbo","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universita\u0300 di Roma , , P. le Aldo Moro 5 , ,","place":["Rome, Italy, I-00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6630-8636","authenticated-orcid":true,"given":"Angela","family":"Corona","sequence":"additional","affiliation":[{"name":"University of Cagliari , , , ,","place":["Cagliari, Monserrato, Italy, SS-554"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Amatore","sequence":"additional","affiliation":[{"name":"Defence Institute for Biomedical Sciences , via di Villa Fonseca 6 , ,","place":["Rome, Italy, 00184"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Grilli","sequence":"additional","affiliation":[{"name":"Defence Institute for Biomedical Sciences , via di Villa Fonseca 6 , ,","place":["Rome, Italy, 00184"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Amoroso","sequence":"additional","affiliation":[{"name":"Defence Institute for Biomedical Sciences , via di Villa Fonseca 6 , ,","place":["Rome, Italy, 00184"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florigio","family":"Lista","sequence":"additional","affiliation":[{"name":"Defence Institute for Biomedical Sciences , via di Villa Fonseca 6 , ,","place":["Rome, Italy, 00184"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Tramontano","sequence":"additional","affiliation":[{"name":"University of Cagliari , , , ,","place":["Cagliari, Monserrato, Italy, SS-554"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1314-9029","authenticated-orcid":true,"given":"Roberta","family":"Costi","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universita\u0300 di Roma , , P. le Aldo Moro 5 , ,","place":["Rome, Italy, I-00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4279-7666","authenticated-orcid":true,"given":"Roberto","family":"Di Santo","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universita\u0300 di Roma , , P. le Aldo Moro 5 , ,","place":["Rome, Italy, I-00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9725-7977","authenticated-orcid":true,"given":"Francesca","family":"Esposito","sequence":"additional","affiliation":[{"name":"University of Cagliari , , , ,","place":["Cagliari, Monserrato, Italy, SS-554"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"issue":"3","key":"2026091109082164200_cit1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","article-title":"Coronavirus\nbiology and replication: implications for SARS-CoV-2","volume":"19","author":"V\u2019kovski","year":"2021","journal-title":"Nat. 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Sci."},{"issue":"3","key":"2026091109082164200_cit6","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.151","article-title":"The SARS-CoV-2\nmain protease (Mpro):\nStructure, function, and emerging therapies for COVID-19","volume":"3","author":"Hu","year":"2022","journal-title":"MedComm"},{"key":"2026091109082164200_cit7","doi-asserted-by":"publisher","first-page":"11779322211025876","DOI":"10.1177\/11779322211025876","article-title":"Structure and Function of Major SARS-CoV-2 and SARS-CoV\nProteins","volume":"15","author":"Gorkhali","year":"2021","journal-title":"Bioinforma. Biol. Insights"},{"key":"2026091109082164200_cit8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11224-022-02089-6","article-title":"Structural differences\nin 3C-like protease (Mpro) from SARS-CoV and\nSARS-CoV-2: molecular insights revealed by Molecular Dynamics Simulations","author":"Parmar","year":"2022","journal-title":"Struct. Chem."},{"key":"2026091109082164200_cit9","doi-asserted-by":"publisher","first-page":"106119","DOI":"10.1016\/j.antiviral.2025.106119","article-title":"The efficiency of high-throughput\nscreening (HTS) and in-silico data analysis during medical emergencies:\nIdentification of effective antiviral 3CLpro inhibitors","volume":"237","author":"Zian","year":"2025","journal-title":"Antiviral Res."},{"issue":"5","key":"2026091109082164200_cit10","doi-asserted-by":"publisher","first-page":"650","DOI":"10.3390\/ph17050650","article-title":"New Thiazolidine-4-One\nDerivatives as SARS-CoV-2 Main Protease Inhibitors","volume":"17","author":"Messore","year":"2024","journal-title":"Pharmaceuticals"},{"key":"2026091109082164200_cit11","doi-asserted-by":"publisher","first-page":"113584","DOI":"10.1016\/j.ejmech.2021.113584","article-title":"Improved\nSARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural\nenhancements, increased solubility, and micellar studies","volume":"222","author":"Vuong","year":"2021","journal-title":"Eur. J. Med. Chem."},{"issue":"11","key":"2026091109082164200_cit12","doi-asserted-by":"publisher","first-page":"3601","DOI":"10.1021\/acs.jcim.3c00282","article-title":"Targeting SARS-CoV-2 Main Protease: A Successful Story\nGuided by an In Silico Drug Repurposing Approach","volume":"63","author":"Ambrosio","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"2026091109082164200_cit13","doi-asserted-by":"publisher","first-page":"115311","DOI":"10.1016\/j.ejmech.2023.115311","article-title":"Broad-spectrum coronavirus 3C-like\nprotease peptidomimetic inhibitors\neffectively block SARS-CoV-2 replication in cells: Design, synthesis,\nbiological evaluation, and X-ray structure determination","volume":"253","author":"Stefanelli","year":"2023","journal-title":"Eur. J. Med. Chem."},{"issue":"6575","key":"2026091109082164200_cit14","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1126\/science.abl4784","article-title":"An oral SARS-CoV-2 Mpro\ninhibitor clinical candidate for the treatment of COVID-19","volume":"374","author":"Owen","year":"2021","journal-title":"Science"},{"issue":"1","key":"2026091109082164200_cit15","doi-asserted-by":"publisher","first-page":"6463","DOI":"10.1038\/s41467-023-42102-y","article-title":"Structure-based development and preclinical evaluation of the SARS-CoV-2\n3C-like protease inhibitor simnotrelvir","volume":"14","author":"Jiang","year":"2023","journal-title":"Nat.\nCommun."},{"issue":"9","key":"2026091109082164200_cit16","doi-asserted-by":"publisher","first-page":"6499","DOI":"10.1021\/acs.jmedchem.2c00117","article-title":"Discovery of S-217622, a Noncovalent\nOral SARS-CoV-2\n3CL Protease Inhibitor Clinical Candidate for Treating COVID-19","volume":"65","author":"Unoh","year":"2022","journal-title":"J. Med. 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Chem."},{"key":"2026091109082164200_cit19","unstructured":"Infectious Diseases Society of America (IDSA).\n          \n          IDSA\nGuidelines on the Treatment and Management of Patients with COVID-19.\n          https:\/\/www.idsociety.org\/practice-guideline\/covid-19-guideline-treatment-and-management\/. accessed 21 Febuary 2026."},{"issue":"15","key":"2026091109082164200_cit20","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1056\/NEJMoa2118542","article-title":"EPIC-HR Investigators.\nOral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19","volume":"386","author":"Hammond","year":"2022","journal-title":"N. Engl. J. 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Pharmacol."},{"key":"2026091109082164200_cit26","doi-asserted-by":"publisher","first-page":"105697","DOI":"10.1016\/j.antiviral.2023.105697","article-title":"Diketo acid\ninhibitors of nsp13 of SARS-CoV-2 block viral replication","volume":"217","author":"Corona","year":"2023","journal-title":"Antiviral Res."},{"issue":"14","key":"2026091109082164200_cit27","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202500205","article-title":"Structure-Activity\nRelationships of New 1-Aryl-1H-Indole Derivatives as SARS-CoV-2 Nsp13\nInhibitors","volume":"20","author":"Madia","year":"2025","journal-title":"ChemMedChem"},{"issue":"1","key":"2026091109082164200_cit28","doi-asserted-by":"publisher","first-page":"2539445","DOI":"10.1080\/14756366.2025.2539445","article-title":"N-alkyl and\nN-benzyl indoles are anti-SARS-CoV-2 agents and nsp13 inhibitors","volume":"40","author":"Albano","year":"2025","journal-title":"J. Enzyme Inhib. Med. Chem."},{"issue":"1","key":"2026091109082164200_cit29","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1080\/14756366.2016.1250755","article-title":"Inhibition\nof Leishmania\ninfantum trypanothione reductase by diaryl sulfide derivatives","volume":"32","author":"Saccoliti","year":"2017","journal-title":"J. Enzyme Inhib. Med. Chem."},{"issue":"3","key":"2026091109082164200_cit30","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3390\/molecules26030771","article-title":"Synthesis\nand Biological Evaluation\nof New Pyrimidine Derivatives as Anticancer Agents","volume":"26","author":"Madia","year":"2021","journal-title":"Molecules"},{"issue":"2","key":"2026091109082164200_cit31","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1021\/acs.jctc.0c01006","article-title":"Accelerating AutoDock4 with GPUs\nand gradient-based local search","volume":"17","author":"Santos-Martins","year":"2021","journal-title":"J. Chem. Theory\nComput."},{"issue":"7811","key":"2026091109082164200_cit32","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from\nSARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"issue":"8","key":"2026091109082164200_cit33","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1021\/acs.oprd.6b00180","article-title":"Palladium-Catalyzed\nSuzuki Reactions in Water with No Added Ligand: Effects of Reaction\nScale, Temperature, pH of Aqueous Phase, and Substrate Structure","volume":"20","author":"Li","year":"2016","journal-title":"Org. Process Res. Dev."},{"issue":"1","key":"2026091109082164200_cit34","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s10637-019-00762-y","article-title":"Discovery\nof a pyrimidine compound endowed with antitumor activity","volume":"38","author":"Taglieri","year":"2020","journal-title":"Invest. 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Med. Chem."},{"issue":"7","key":"2026091109082164200_cit39","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02624-24","article-title":"Structural\nbasis for varying drug\nresistance of SARS-CoV-2 Mpro E166 variants","volume":"16","author":"Esler","year":"2025","journal-title":"mBio"},{"issue":"2","key":"2026091109082164200_cit40","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1021\/acsptsci.5c00681","article-title":"Characterization of the Cross-Resistance\nof SARS-CoV-2 Main Protease Inhibitors, Ibuzatrelvir, Ensitrelvir,\nand Nirmatrelvir","volume":"9","author":"Tan","year":"2026","journal-title":"ACS Pharmacol. Transl. Sci."},{"issue":"23","key":"2026091109082164200_cit41","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adv8875","article-title":"Strategy\nto overcome a nirmatrelvir resistance mechanism in the SARS-CoV-2\nnsp5 protease","volume":"11","author":"Neilsen","year":"2025","journal-title":"Sci. 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