Design, synthesis and biological activity of coumarin-chalcone hybrid derivatives as phosphodiesterase type II (PDE2) inhibitors

Coumarin and chalcone are two compounds that have been extensively studied for their neuroprotective effects. Coumarin is known for its ability to inhibit MAO activity in the brain and reduce central nervous system damage caused by dopamine degradation. Chalcone, on the other hand, has gained attention due to its potential medicinal value, including free radical scavenging, anti-inflammatory, and neuroprotective properties. Both compounds have shown promise in the development of treatments for neurodegenerative diseases like Alzheimer's disease. In this study, we designed and synthesized 36 coumarin-chalcone heteroderivatives based on the principle of structure hybridization. We then evaluated the inhibitory effects of these compounds on phosphodiesterase II (PDE2) at the enzyme level and analyzed their structure-activity relationship. Among the hybrid derivatives, compounds 2b, 3a, 3i, 3m, and 1l demonstrated significant inhibitory activity on PDE2, with IC50 values of 24.46 mu M, 16.82 mu M, 28.13 mu M, 21.88 mu M, and 29.72 mu M, respectively. This paper presents the design, synthesis, and biological evaluation of coumarin-chalcone hybrid derivatives for their potential as PDE2 inhibitors.