{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T05:53:14Z","timestamp":1787982794294,"version":"build-2784847793"},"reference-count":27,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T00:00:00Z","timestamp":1706832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Designing novel candidates as potential antibacterial scaffolds has become crucial due to the lack of new antibiotics entering the market and the persistent rise in multidrug resistance. Here, we describe a new class of potent antibacterial agents based on a 5\u2010aryl\u2010<jats:italic>N<\/jats:italic><jats:sup>2<\/jats:sup>,<jats:italic>N<\/jats:italic><jats:sup>4<\/jats:sup>\u2010dibutylpyrimidine\u20102,4\u2010diamine scaffold. Structural optimization focused on the 5\u2010aryl moiety and the bioisosteric replacement of the side chain linker atom. Screening of the synthesized compounds focused on a panel of bacterial strains, including gram\u2010positive <jats:italic>Staphylococcus aureus<\/jats:italic> strains (Newman MSSA, methicillin\u2010 and vancomycin\u2010resistant), and the gram\u2010negative <jats:italic>Escherichia coli<\/jats:italic> (\u0394AcrB strain). Several compounds showed broad\u2010spectrum antibacterial activity with compound <jats:bold>12<\/jats:bold>, bearing a 4\u2010chlorophenyl substituent, being the most potent among this series of compounds. This frontrunner compound revealed a minimum inhibitory concentration (MIC) value of 1\u2009\u00b5g\/mL against the <jats:italic>S. aureus<\/jats:italic> strain (Mu50 methicillin\u2010resistant <jats:italic>S. aureus<\/jats:italic>\/vancomycin\u2010intermediate <jats:italic>S. aureus<\/jats:italic>) and an MIC of 2\u2009\u00b5g\/mL against other tested strains. The most potent derivatives were further tested against a wider panel of bacteria and evaluated for their cytotoxicity, revealing further potent activities toward <jats:italic>Streptococcus pneumoniae, Enterococcus faecium<\/jats:italic>, and <jats:italic>Enterococcus faecalis<\/jats:italic>. To explore the mode of action, compound <jats:bold>12<\/jats:bold> was tested in a macromolecule inhibition assay. The obtained data were supported by the safety profile of compound <jats:bold>12<\/jats:bold>, which possessed an IC<jats:sub>50<\/jats:sub> of 12.3\u2009\u00b5g\/mL against HepG2 cells. The current results hold good potential for a new class of extended\u2010spectrum antibacterial agents.<\/jats:p>","DOI":"10.1002\/ardp.202300656","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T09:00:42Z","timestamp":1706864442000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Development and evaluation of 2,4\u2010disubstituted\u20105\u2010aryl pyrimidine derivatives as antibacterial agents"],"prefix":"10.1002","volume":"357","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0407-7645","authenticated-orcid":false,"given":"Hend","family":"Khalifa","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology German University in Cairo Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sari","family":"Rasheed","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research Saarland University Campus Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF), Partner Site Hannover\u2010Braunschweig Saarbrucken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3991-2800","authenticated-orcid":false,"given":"J\u00f6rg","family":"Haupenthal","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research Saarland University Campus Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research Saarland University Campus Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF), Partner Site Hannover\u2010Braunschweig Saarbrucken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine M.","family":"Mandour","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology German University in Cairo Cairo Egypt"},{"name":"School of Life and Medical Sciences University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7433-261X","authenticated-orcid":false,"given":"Ashraf H.","family":"Abadi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology German University in Cairo Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5065-8634","authenticated-orcid":false,"given":"Matthias","family":"Engel","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Medicinal Chemistry Saarland University Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research Saarland University Campus Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF), Partner Site Hannover\u2010Braunschweig Saarbrucken Germany"},{"name":"Department of Pharmacy Saarland University Saarbr\u00fccken Germany"},{"name":"Helmholtz International Lab for Anti\u2010infectives Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna K. H.","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research Saarland University Campus Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF), Partner Site Hannover\u2010Braunschweig Saarbrucken Germany"},{"name":"Department of Pharmacy Saarland University Saarbr\u00fccken Germany"},{"name":"Helmholtz International Lab for Anti\u2010infectives Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1326-4219","authenticated-orcid":false,"given":"Mohammad","family":"Abdel\u2010Halim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology German University in Cairo Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7374-6992","authenticated-orcid":false,"given":"Mostafa M.","family":"Hamed","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research Saarland University Campus Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2019.10.008"},{"key":"e_1_2_6_3_1","volume":"8","author":"Chan S.","year":"2020","journal-title":"Cochrane Database Syst. 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