Research Article DFT Investigations and Molecular Docking as Potent Inhibitors of SARS-CoV-2 Main Protease of Novel Pyrimidine Dione Derivatives WesamS.Shehab , 1,2 JalalHasanMohammed, 3 Naja Magdy, 2 WaelA.Zordok , 1 Mariusz Jaremko, 4 andDoaaA.Elsayed 1,2 1 Department of Chemistry, Faculty of Science, Zagazig University, Zagazig 44519, Egypt 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Farahidi University, Baghdad, Iraq 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Karbala, Karbala, Iraq 4 Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Tuwal 23955-6900, Saudi Arabia Correspondence should be addressed to Wesam S. Shehab; dr.wesamshehab@gmail.com Received 20 May 2024; Revised 15 June 2025; Accepted 21 July 2025 Academic Editor: Harleen Khatra Copyright © 2025 Wesam S. Shehab et al. Biochemistry Research International published by John Wiley & Sons Ltd. Tis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Te global outbreak of SARS-CoV-2 has emerged as a major public health crisis due to its rapid transmission and signifcant morbidity and mortality rates. In response, there is an urgent need to discover novel antiviral agents targeting key viral proteins. In this study, a new series of pyrimidine-2,4-dione derivatives was synthesized from barbituric acid and its thio analog, aiming to explore their potential inhibitory activity against the SARS-CoV-2 main protease (Mpro). Te synthesis involved 1,4-addition and cyclodehydration reactions, yielding novel pyran and condensed pyrimidine derivatives. Te chemical structures were confrmed using various spectroscopic techniques. Molecular docking studies were performed using MOE software (version 2022) targeting Mpro (PDB ID: 6LU7), revealing favorable binding afnities for several compounds. Compound 9 showed the best docking score (−12.70kcal/mol), followed by Compound 4 (−12.38kcal/mol) and Compound 11 (−12.13kcal/mol), with key interactions involving residues such as Asn142, His41, and Glu166. DFT calculations were carried out to evaluate electronic properties, including energy gap (ΔE), global hardness (η), and softness (σ), indicating that Compound 10 was the most reactive with notable HOMO–LUMO characteristics. Additionally, the synthesized compounds were screened for drug- likeness based on Lipinski’s rule of fve and ADME parameters. Overall, the study identifes promising pyrimidine-based inhibitors of SARS-CoV-2 Mpro and provides valuable insights for further optimization and development of potential antiviral agents. Keywords: ADME properties; COVID-19; diphenyl derivative; imidazolopyrimidine; pyranopyrimidine; pyridotriazine 1.Introduction Since the emergence of SARS-CoV-2 in late 2019, the world has faced an unprecedented public health challenge marked by high morbidity and mortality rates. Te virus, classifed as a positive-sense single-stranded RNA virus of the Coro- naviridae family, encodes several structural and non- structural proteins essential for viral replication and pathogenesis. Among these, the main protease (Mpro or 3CLpro) and RNA-dependent RNA polymerase (RdRp) have emerged as validated drug targets due to their in- dispensable role in processing viral polyproteins and RNA synthesis, respectively [1–5]. Despite signifcant global ef- forts, the current therapeutic arsenal remains limited, and the emergence of new variants underscores the urgent need to develop novel antiviral agents. Structure-based drug design (SBDD) and in silico screening have become in- dispensable tools for identifying promising lead compounds targeting SARS-CoV-2 proteins [6, 7]. Several chemical scafolds have been explored for their potential antiviral Wiley Biochemistry Research International Volume 2025, Article ID 7961294, 21 pages https://doi.org/10.1155/bri/7961294