<i>De Novo</i> Drug Design, Synthesis, Biological Evaluation, and Structural Examination of Novel Coumarin-Based Pyrimidine Co-Drugs Accompanied by Molecular Docking and DFT Studies

In this research, we synthesized novel coumarin-pyrimidine hybrid molecules and studied their antioxidant properties by using the DPPH radical scavenging assay. Different computational techniques (3DQSAR, pharmacophore modeling, molecular docking, MMGBSA, and ADMET) were used to validate the synthesized compounds further. The structures of all synthesized compounds were confirmed by ¹H NMR and ¹³C NMR spectral analysis. The compound <b>3b</b> showed the best IC₅₀ values of 11.68 μM in DPPH assay and 17.51 μM in H₂O₂ assay. Compound <b>6b</b> showed the best docking score of -6.49 kcal/mol compared to that of the reference compound. Further, to confirm the formation of a novel linkage, the electronic and structural properties of the lead-most-active compound <b>6b</b>, reactant 1, and reactant 2 were studied by Density Functional Theory (DFT) calculations on the Gaussian 09 software package. The key findings of the <i>in vitro</i> antioxidant and molecular docking results, as well as the analysis, demonstrated that the synthesized compounds have potential antioxidant activity and can be further optimized to serve as lead compounds. This study reveals that the coumarin-pyrimidine-based molecular hybrid is potent in the DPPH assay and can be further utilized to treat oxidative stress disorders.