Design, synthesis, and biological evaluation of coumestrol-based inhibitors targeting phosphodiesterase type 2

The level of phosphodiesterase type 2 (PDE2) in the body is closely associated with human health. From the L6000 natural compound library, the natural coumarin compound coumestrol was identified as possessing PDE2 inhibitory activity. Using computer-aided drug design software, we modified and synthesized coumestrol derivatives and subsequently evaluated their PDE2 inhibitory activity. Among the synthesized compounds, B2-1 exhibited the strongest activity, with an IC₅₀ value of 1.09 ± 0.07 μM, approximately 7 times higher than that of coumestrol. Finally, ADMET prediction of coumestrol and B2-1 found that B2-1’s ability is equal to or better than coumestrol in terms of intestinal absorption, hepatotoxicity, protein binding, and so on.