Design, Synthesis, In Vitro Evaluation of New Tetrahydrooxazolo [5′,4′:4,5]Pyrimido[1,2-a]Azepinone Derivatives as Anticancer Agents

A total of 48 tetrahydrooxazolo-[5′,4′:4,5]pyrimido[1,2-a]azepinones were designed and synthesized from a scaffold hopping approach. All compounds were confirmed by analysis using ¹H NMR, ¹³C NMR, and HRMS techniques. The synthesized compounds were evaluated against the human cancer cell lines (HeLa, MCF-7, A549) in vitro, and the structure–activity relationships were summarized. The compound E43 exhibited the best inhibitory activity against HeLa, MCF-7, A549, displaying IC₅₀ values of 1.48 ± 0.13, 3.01 ± 0.09, and 5.11 ± 0.13 μM. Molecular docking indicated that compound E43 may bind to protein (PDB:6FEX) via hydrogen bond and π stacking. Further, molecular dynamics simulations indicated a relatively low binding free energy (−40.06 kJ·mol⁻¹) of compound E43 with protein. In conclusion, these findings suggested that E43 is promising as a potential novel anticancer drug candidate worthy of further investigation.