{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:31:42Z","timestamp":1790476302462,"version":"4.1.0"},"reference-count":96,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004242","name":"Princess Nourah bint Abdulrahman University","doi-asserted-by":"crossref","award":["PNURSP2025R89"],"award-info":[{"award-number":["PNURSP2025R89"]}],"id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Derivatives of Pyrido[2,3-d]pyrimidine-6-carboxylate are promising multi-target scaffolds. This study focused on synthesizing 16 amino-functionalized derivatives and evaluating their dual anticancer and antibacterial activities, supported by mechanistic and computational analyses. Objectives: Design and synthesize derivatives, evaluate cytotoxicity against HeLa, HepG-2, and MCF-7 (selectivity against WI-38), investigate EGFRWT and EGFRT790M inhibition, assess cell cycle, apoptosis, and migration effects, antibacterial efficacy against E. coli and P. aeruginosa, and perform in silico ADMET, docking, molecular dynamics, DFT, and antiviral predictions. Methods: Synthesized 16 derivatives; tested for cytotoxicity, EGFR inhibition, cell cycle, apoptosis, migration; assessed antibacterial activity; performed ADMET profiling, molecular docking, molecular dynamics, and DFT calculations. Results: Derivatives 1, 2, and 7 showed highest cytotoxicity (IC50 = 3.98\u201317.52 \u03bcM; WI-38 IC50 = 64.07\u201381.65 \u03bcM). Compound 1 potently inhibited EGFRWT (IC50 = 0.093 \u03bcM) and EGFRT790M (IC50 = 0.174 \u03bcM), induced G0\/G1 arrest (74.86%) and apoptosis (26.37%), and reduced MCF-7 migration (69.63%). Moderate antibacterial activity observed (MIC = 50 \u03bcg\/mL). ADMET indicated favorable pharmacokinetics, low CYP inhibition, negative mutagenicity, and oral toxicity class III. Molecular dynamics confirmed stable binding (EGFRWT RMSD 3 \u00c5; EGFRT790M 3.5\u20134.6 \u00c5) with persistent hydrogen bonds. In silico antiviral evaluation suggested strong binding to HCV NS5A (\u20139.36 kcal\/mol), SARS-CoV-2 Mpro (\u20139.82 kcal\/mol), and E.coli DNA gyrase (\u201310.25 kcal\/mol). Conclusions: Compound 1 exhibits dual anticancer and antibacterial activity, supported by mechanistic and computational analyses, highlighting pyrido[2,3-d]pyrimidines as promising multi-target therapeutic scaffolds.<\/jats:p>","DOI":"10.3390\/ph18101472","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T13:52:46Z","timestamp":1759240366000},"page":"1472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Innovative Amino-Functionalization of Pyrido[2,3-d]pyrimidine Scaffolds for Broad Therapeutic Applications Supported by Computational Analyses"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3841-6122","authenticated-orcid":false,"given":"Hagar S.","family":"El-Hema","sequence":"first","affiliation":[{"name":"Basic Science Department (Chemistry), Thebes Higher Institute for Engineering, Thebes Academy, Maadi 11434, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5385-4220","authenticated-orcid":false,"given":"Haitham E.","family":"Shehata","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Hawata","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6159-5333","authenticated-orcid":false,"given":"Eman S.","family":"Nossier","sequence":"additional","affiliation":[{"name":"Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt"},{"name":"The National Committee of Drugs, Academy of Scientific Research and Technology, Cairo 11516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5312-4870","authenticated-orcid":false,"given":"Ahmed F.","family":"El-Sayed","sequence":"additional","affiliation":[{"name":"Microbial Genetics Department, Biotechnology Research Institute, National Research Centre, Giza 12622, Egypt"},{"name":"Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6372-7141","authenticated-orcid":false,"given":"Najla A.","family":"Altwaijry","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-319X","authenticated-orcid":false,"given":"Asmaa","family":"Saleh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-2745","authenticated-orcid":false,"given":"Modather F.","family":"Hussein","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science, Jouf University, P.O. Box 2014, Sakaka, Aljouf 72341, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Sabry","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Manufacturing, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), 6th of October City, P.O. Box 77, Giza 12591, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel A.-H.","family":"Abdel-Rahman","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1002\/ijc.35278","article-title":"The GLOBOCAN 2022 cancer estimates: Data sources, methods, and a snapshot of the cancer burden worldwide","volume":"156","author":"Filho","year":"2025","journal-title":"Int. J. 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