Uracil-Quinazoline Hybrids: Cytotoxicity, Docking, MD, and DFT Studies.

INTRODUCTION: Cancer remains a major cause of mortality worldwide; therefore, research continues to focus on the development of more effective therapeutic agents. METHODS: In this study, the cytotoxic effects of a series of uracil-quinazoline hybrids were evaluated against A549 (lung cancer) and HepG2 (hepatocellular carcinoma) cell lines using the MTT assay. RESULTS: The biological results demonstrated that several of the studied hybrids exhibited significant cytotoxic activity against both A549 and HepG2 cell lines compared to the reference drugs Erlotinib (IC50 = 35.5 ± 0.4 μM for A549; 13.1 ± 0.2 μM for HepG2) and Cisplatin (IC50 = 15.4 ± 1.6 μM for A549; 15.9 ± 1.8 μM for HepG2). Among the studied hybrids, compound 3f showed the highest anti-proliferative activity against A549 cells, with an IC50 value of 5.4 ± 1.3 μM, while compounds 3g and 3i displayed superior cytotoxic activity against HepG2 cells, with IC50 values of 6.9 ± 3.0 μM and 3.3 ± 1.7 μM, respectively. Molecular docking studies and Molecular Dynamics (MD) simulations revealed that the binding interactions of the active hybrids within the Cyclin-Dependent Kinase 2 (CDK2) active site were consistent with the biological findings, suggesting CDK2 as a potential molecular target. Furthermore, Density Functional Theory (DFT) calculations were performed to theoretically evaluate the Frontier Molecular Orbital (HOMO and LUMO) energy levels, chemical reactivity, and molecular stability of selected hybrids. DISCUSSION: These findings highlight the therapeutic potential of uracil-quinazoline hybrids, particularly compounds 3f, 3g, and 3i, as potent inhibitors of lung and liver cancer cell growth, with activities superior to those of standard drugs. The consistency between experimental cytotoxicity results, molecular docking, MD simulation, and DFT analyses supports CDK2 as a plausible molecular target and provides insight into the structure-activity relationships governing their anticancer effects. This integrated computational-experimental approach strengthens the rationale for further development of these hybrids as targeted anticancer agents. CONCLUSION: These findings provide a strong foundation for future optimization and in vivo evaluation of uracil-quinazoline derivatives as targeted cancer therapeutics.