{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:35:57Z","timestamp":1785429357069,"version":"3.56.0"},"reference-count":66,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Next Generation EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases","award":["PE00000007"],"award-info":[{"award-number":["PE00000007"]}]},{"name":"Next Generation EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases","award":["INF-ACT"],"award-info":[{"award-number":["INF-ACT"]}]},{"name":"Next Generation EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases","award":["Spoke 5"],"award-info":[{"award-number":["Spoke 5"]}]},{"name":"Next Generation EU-MUR PRIN 2022 project","award":["20228NPP2Y"],"award-info":[{"award-number":["20228NPP2Y"]}]},{"DOI":"10.13039\/501100004271","name":"Ateneo 2024","doi-asserted-by":"publisher","award":["RG124190BB0EB5C9"],"award-info":[{"award-number":["RG124190BB0EB5C9"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RG124190BB0EB5C9"],"award-info":[{"award-number":["RG124190BB0EB5C9"]}],"id":[{"id":"https:\/\/ror.org\/053kevk63","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The SARS-CoV-2 pandemic has posed a tremendous burden globally, highlighting the urgent need for new effective antivirals that are possibly useful against future emerging Coronaviruses (hCoVs). In this context, major efforts were focused on the inhibition of highly conserved and essential targets playing a pivotal role in viral replication. Among them, SARS-CoV-2 nsp13 stands out, being the most conserved enzyme within hCoVs. Following our previous reports describing the identification of indole-based diketo acid (DKA) derivatives as SARS-CoV-2 nsp13 inhibitors endowed with antiviral activity, we applied a scaffold hopping strategy to identify new nsp13 inhibitors. Therefore, we investigated a series of 4-phenyl pyrrolyl DKAs and their structural analogs characterized by molecular simplification or DKA isosteric replacement. The derivatives showed potency against both nsp13-associated activities exhibiting measurable IC50s in the low micromolar\/submicromolar range, highlighting a promising dual inhibitory profile accordingly. Structure\u2013activity relationship (SAR) studies were performed, highlighting the main structural features increasing the activity of the different compound classes. Interestingly, SAR trends were confirmed in the presence of the BSA\/TCEP system despite variations in potency. To shed light on the interaction of the best acting compounds 13b, 15a, and 17d, docking studies were performed, suggesting a putative binding mode in agreement with our previous findings.<\/jats:p>","DOI":"10.3390\/molecules31132376","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T10:43:11Z","timestamp":1783334591000},"page":"2376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2013Activity Relationships of Pyrrolyl-Containing Diketo Acid and Non-Diketo Acid Derivatives as Inhibitors of SARS-CoV-2 nsp13-Associated Activities"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4531-3612","authenticated-orcid":false,"given":"Elisa","family":"Patacchini","sequence":"first","affiliation":[{"name":"Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universit\u00e0 di Roma, p.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-5503","authenticated-orcid":false,"given":"Francesco","family":"Saccoliti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Health and Health Professions, Link Campus University, Via del Casale di San Pio V 44, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4546-6449","authenticated-orcid":false,"given":"Roberta","family":"Emmolo","sequence":"additional","affiliation":[{"name":"Laboratorio di Virologia Molecolare, Dipartimento di Scienze della Vita e dell\u2019Ambiente Sezione Biomedica, Universit\u00e0 di Cagliari, Cittadella Universitaria di Monserrato, SS554, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5724-612X","authenticated-orcid":false,"given":"Valentina Noemi","family":"Madia","sequence":"additional","affiliation":[{"name":"Department of Science, Universit\u00e0 degli Studi Roma Tre, Viale Guglielmo Marconi 446, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7723-2201","authenticated-orcid":false,"given":"Emanuele","family":"Cara","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universit\u00e0 di Roma, p.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6850-528X","authenticated-orcid":false,"given":"Aurora","family":"Albano","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universit\u00e0 di Roma, p.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6630-8636","authenticated-orcid":false,"given":"Angela","family":"Corona","sequence":"additional","affiliation":[{"name":"Laboratorio di Virologia Molecolare, Dipartimento di Scienze della Vita e dell\u2019Ambiente Sezione Biomedica, Universit\u00e0 di Cagliari, Cittadella Universitaria di Monserrato, SS554, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-0980","authenticated-orcid":false,"given":"Enzo","family":"Tramontano","sequence":"additional","affiliation":[{"name":"Laboratorio di Virologia Molecolare, Dipartimento di Scienze della Vita e dell\u2019Ambiente Sezione Biomedica, Universit\u00e0 di Cagliari, Cittadella Universitaria di Monserrato, SS554, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4279-7666","authenticated-orcid":false,"given":"Roberto","family":"Di Santo","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universit\u00e0 di Roma, p.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Costi","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, \u201cSapienza\u201d Universit\u00e0 di Roma, p.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated 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