Design, synthesis, and biological evaluation of novel urolithins derivatives as potential phosphodiesterase II inhibitors

Long Tang,Guoqiang Song,Yajing Wang,Ying Tan,Xiaoqing Feng,Xianfeng Huang,Ziheng Zhuang,Jianchun Jiang,Yan Xia

doi:10.1038/s41598-021-03194-y

Abstract

A series of urolithins derivatives were designed and synthesized, and their structures have been confirmed by 1H NMR, 13C NMR, and HR-MS. The inhibitory activity of these derivatives on phosphodiesterase II (PDE2) was thoroughly studied with 3-hydroxy-8-methyl-6H-benzo[C]chromen-6-one and 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[C] chromen-6-one as the lead compounds. The biological activity test showed that compound 2e had the best inhibitory activity on PDE2 with an IC50 of 33.95 μM. This study provides a foundation for further structural modification and transformation of urolithins to obtain PDE2 inhibitor small molecules with better inhibitory activity.

Highlights

A series of urolithins derivatives were designed and synthesized, and their structures have been confirmed by 1H NMR, 13C NMR, and HR-MS
It was been reported that Ellagic acid (EA) can reduce the formation of advanced glycation end products inducing autophagy cells which protect the hippocampus of brain, suggesting great therapeutic potential in the treatment of progressive neurodegenerative diseases such as typical Alzheimer’s disease (AD) and Parkinson’s disease (PD)[7]
The general pathways for synthesizing 3-hydroxy-8-methyl-6H-benzo[c]chromen6-one derivatives 2 and 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one derivatives 4 are shown in Schemes 133 and 234, respectively

Summary

Introduction

A series of urolithins derivatives were designed and synthesized, and their structures have been confirmed by 1H NMR, 13C NMR, and HR-MS. The inhibitory activity of these derivatives on phosphodiesterase II (PDE2) was thoroughly studied with 3-hydroxy-8-methyl-6H-benzo[C]chromen6-one and 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[C] chromen-6-one as the lead compounds. This study provides a foundation for further structural modification and transformation of urolithins to obtain PDE2 inhibitor small molecules with better inhibitory activity. Urolithins have become bioactive markers of EA e xposure[2,10,11,12,13,14], and since it is bioavailable, it shows great potential in the treatment of progressive neurodegenerative diseases[15,16,17,18,19,20,21]. The lack of proven treating methods continues to be one of the biggest challenges for the effective intervention and reversal of the increasing occurrence and development of AD today

Methods

Results

Conclusion