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In response, there is an urgent need to discover novel antiviral agents targeting key viral proteins. In this study, a new series of pyrimidine\u20102,4\u2010dione derivatives was synthesized from barbituric acid and its thio analog, aiming to explore their potential inhibitory activity against the SARS\u2010CoV\u20102 main protease (Mpro). The synthesis involved 1,4\u2010addition and cyclodehydration reactions, yielding novel pyran and condensed pyrimidine derivatives. The chemical structures were confirmed using various spectroscopic techniques. Molecular docking studies were performed using MOE software (version 2022) targeting Mpro (PDB ID: 6LU7), revealing favorable binding affinities for several compounds. Compound 9 showed the best docking score (\u221212.70\u2009kcal\/mol), followed by Compound 4 (\u221212.38\u2009kcal\/mol) and Compound 11 (\u221212.13\u2009kcal\/mol), with key interactions involving residues such as Asn142, His41, and Glu166. DFT calculations were carried out to evaluate electronic properties, including energy gap (\u0394E), global hardness (\u03b7), and softness (\u03c3), indicating that Compound 10 was the most reactive with notable HOMO\u2013LUMO characteristics. Additionally, the synthesized compounds were screened for drug\u2010likeness based on Lipinski\u2019s rule of five and ADME parameters. Overall, the study identifies promising pyrimidine\u2010based inhibitors of SARS\u2010CoV\u20102 Mpro and provides valuable insights for further optimization and development of potential antiviral agents.<\/jats:p>","DOI":"10.1155\/bri\/7961294","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T06:36:38Z","timestamp":1754980598000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["DFT Investigations and Molecular Docking as Potent Inhibitors of SARS\u2010CoV\u20102 Main Protease of Novel Pyrimidine Dione Derivatives"],"prefix":"10.1155","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5246-3491","authenticated-orcid":false,"given":"Wesam S.","family":"Shehab","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jalal Hasan","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naja","family":"Magdy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1717-1028","authenticated-orcid":false,"given":"Wael A.","family":"Zordok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariusz","family":"Jaremko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8139-8548","authenticated-orcid":false,"given":"Doaa A.","family":"Elsayed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"e_1_2_11_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2021.08.041"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1166\/jnn.2020.18955"},{"key":"e_1_2_11_3_2","doi-asserted-by":"crossref","unstructured":"KhaerunnisaS. 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