Abstract
A series of symmetric and asymmetric diarylpentanoids based on N-isopropyl-4-piperidone were rationally designed and synthesized through a Claisen–Schmidt condensation reaction. This was done to investigate their potential as anticancer and anti-inflammatory agents. The synthesized compounds were evaluated for cytotoxic activity against the MCF-7 breast cancer cell line, as well as for nitric oxide inhibitory activity in LPS-stimulated RAW264.7 macrophages. Structure-activity relationship analysis revealed that the presence of electron-donating substituents and asymmetric aryl substitutions significantly enhanced biological activity. Among the synthesized derivatives, compound KB2d exhibited the strongest anticancer activity, with an IC(50) value of 1.54 µM, while compound KB2c demonstrated promising anti-inflammatory activity, with an IC(50) value of 2.51 µM. To understand the molecular basis of these activities, molecular docking simulations and 200 ns molecular dynamics were conducted on aromatase and PDE4D protein targets. The leading compound, KB2d, showed stable binding behavior, low ligand RMSD oscillations, and favorable binding free energy (ΔG_bind ≈ −33 kcal mol(−1)) as calculated using the MM-PBSA method. These findings suggest that asymmetric N-isopropyl-4-piperidone diarylpentanoids represent promising structural frameworks for the further development of anticancer and anti-inflammatory agents.