Design, synthesis of urolithin A, the metabolite of ellagitannins, and its biological activity of phosphodiesterase II (PDE2) inhibitors

Abstract Urolithin A (UA), a dietary polyphenol metabolite, exhibits bioactivity across diverse domains, including antioxidant, anti-inflammatory, anticancer, muscle health improvement, and neuroprotective effects. Due to its prominent bioactivity in central nervous system protection, UA has emerged as a promising lead compound for developing therapeutic agents against neurodegenerative disorders. However, limitations such as poor activity, low bioavailability, and instability necessitate targeted structural modifications. In this study, guided by relevant literature, UA was utilized as the core scaffold. Structural modifications involved replacing the 8-hydroxy group with an amino group and etherifying the 3-hydroxy group. Discovery Studio software was employed for compound design and molecular docking screening. Subsequently, the target compounds were synthesized and subjected to in vitro enzymatic activity assays. Our group designed 35 compounds and synthesized them using 2-bromo-5-aminobenzoic acid as the starting material. This yielded 35 intermediate compounds (3-hydroxyl-modified 8-amino-urolithin A series) and 35 final derivatives (3-hydroxyl-modified 8-amino-urolithin A series). The inhibitory activity of the synthesized products was evaluated using a Phosphodiesterase Assay Kit. Among the derivatives, compounds D24, D31, and E31 demonstrated significant inhibitory activity against PDE2, with half-maximal inhibitory concentration (IC₅₀) values of 0.31 μM, 0.018 μM, and 0.7 μM, respectively. Here, we report the design and synthesis of 3-hydroxyl-modified 8-amino-urolithin A derivatives and the biological evaluation of their activity against PDE2.