DFT Investigations and Molecular Docking as Potent Inhibitors of SARS‐CoV‐2 Main Protease of Novel Pyrimidine Dione Derivatives

The global outbreak of SARS-CoV-2 has emerged as a major public health crisis due to its rapid transmission and significant 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). The synthesis involved 1,4-addition 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 (-12.70 kcal/mol), followed by Compound 4 (-12.38 kcal/mol) and Compound 11 (-12.13 kcal/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 five and ADME parameters. Overall, the study identifies promising pyrimidine-based inhibitors of SARS-CoV-2 Mpro and provides valuable insights for further optimization and development of potential antiviral agents.