{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T07:28:07Z","timestamp":1768721287710,"version":"3.49.0"},"reference-count":16,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["22\u201017118S"],"award-info":[{"award-number":["22\u201017118S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    The COVID\u201019 pandemic, caused by the highly transmissible SARS\u2010CoV\u20102 virus, has highlighted the urgent need for effective small\u2010molecule antivirals. To date, only a few such agents, including molnupiravir and remdesivir, have been approved by the FDA. In our previous study, a novel class of SARS\u2010CoV\u20102 RNA\u2010dependent RNA polymerase (RdRp) inhibitors based on an\n                    <jats:italic>N<\/jats:italic>\n                    ,\n                    <jats:italic>N<\/jats:italic>\n                    \u2032\u2010diphenylurea scaffold was identified; however, these compounds exhibited poor aqueous solubility and significant cytotoxicity. Herein, the design, synthesis, and evaluation of twenty\u2010seven new derivatives aimed at improving solubility and reducing cytotoxicity through targeted scaffold modifications are reported. Seven analogs display enhanced aqueous solubility (kinetic solubility\u2009&gt;\u200910\u2009\u00b5M), and nine compounds show residual RdRp activity (RA\u2014determined at 10\u2009\u03bcM concentration of screened compounds) below 50%, with the most potent analog achieving an RA value of 34%. Despite these improvements, cytotoxicity remains a limitation across the series. These findings provide valuable structure\u2013activity relationship insights and direct ongoing optimization efforts toward developing less toxic, soluble RdRp inhibitors with improved antiviral profiles.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500644","type":"journal-article","created":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T06:47:41Z","timestamp":1763880461000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Allosteric Inhibitors of SARS\u2010CoV\u20102 RNA\u2010Dependent RNA Polymerase Based on\n                    <i>N<\/i>\n                    ,\n                    <i>N\u2032<\/i>\n                    \u2010Diphenylurea"],"prefix":"10.1002","volume":"21","author":[{"given":"Artem","family":"Chayka","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 2 Prague 6 160 00 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mat\u011bj","family":"Danda","sequence":"additional","affiliation":[{"name":"Department of Biotechnology University of Chemistry and Technology, Prague  Technick\u00e1 5 Prague 6 166 28 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Al\u017eb\u011bta","family":"Dost\u00e1lkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biotechnology University of Chemistry and Technology, Prague  Technick\u00e1 5 Prague 6 166 28 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vojt\u011bch","family":"Spiwok","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology University of Chemistry and Technology, Prague  Technick\u00e1 5 Prague 6 166 28 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lamija","family":"Zijadic","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology University of Chemistry and Technology, Prague  Technick\u00e1 5 Prague 6 166 28 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Klime\u0161ov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biotechnology University of Chemistry and Technology, Prague  Technick\u00e1 5 Prague 6 166 28 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Kapisheva","sequence":"additional","affiliation":[{"name":"Department of Biotechnology University of Chemistry and Technology, Prague  Technick\u00e1 5 Prague 6 166 28 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michala","family":"Zgarbov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 2 Prague 6 160 00 Czech Republic"},{"name":"Department of Genetics and Microbiology Faculty of Sciences Charles University  Vini\u010dn\u00e1 5 Prague 2 128 44 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 2 Prague 6 160 00 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Ruml","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology University of Chemistry and Technology, Prague  Technick\u00e1 5 Prague 6 166 28 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5645-8227","authenticated-orcid":false,"given":"Michaela","family":"Rumlov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biotechnology University of Chemistry and Technology, Prague  Technick\u00e1 5 Prague 6 166 28 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4654-679X","authenticated-orcid":false,"given":"Zlatko","family":"Janeba","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 2 Prague 6 160 00 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,22]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"1073","volume":"31","author":"Haileamlak A.","year":"2021","journal-title":"Ethiop. 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