Design, synthesis and biological activity of 8-hydroxy modified urolithin A derivatives as phosphodiesterase type II (PDE2) inhibitors

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-02-21 DOI:10.1016/j.bmc.2025.118127

Feng Zhou, Xiaoqing Feng , Zhongqiu Xu, Fen Yan, Guoqiang Song, Long Tang

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Abstract

Urolithin A (UA) is a naturally occurring polyphenolic compound.Due to its remarkable efficacy in safeguarding the central nervous system, UA has emerged as a promising candidate for drug development targeting neurodegenerative diseases such as Alzheimer’s. However, the source of UA is limited and the activity of UA to inhibit PDE2 needs to be further improved. Therefore, this study will be optimized on the basis of UA to seek PDE2 inhibitors with better activity.

In this study, we designed a series of UA derivatives based on 4HTX as the target protein and UA as the lead compound, utilizing the binding crystal structures of 4HTX and BAY60-7550 as references. After thorough screening, we successfully identified the 8-hydroxyl group as the precise site of modification. Utilizing 2-bromo-5-hydroxybenzoic acid as our primary raw material, we synthesized a series of the 8-hydroxyl modified UA. Subsequently, we evaluated the inhibitory activity of these synthesized UA derivatives using a phosphodiesterase assay kit. Ultimately, we screened a total of 34 derivatives; among them, compounds 1f, 1q, 2d, and 2j exhibited significant inhibitory activity against PDE2 with half-maximal inhibitory concentrations of 3.05 μM, 0.67 μM, 0.57 μM, and 4.96 μM, respectively.

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8-羟基修饰尿素A衍生物磷酸二酯酶II型抑制剂的设计、合成及生物活性研究

尿素A （UA）是一种天然存在的多酚化合物。由于其在保护中枢神经系统方面的显着功效，UA已成为针对阿尔茨海默氏症等神经退行性疾病的药物开发的有希望的候选药物。然而，UA的来源有限，UA抑制PDE2的活性有待进一步提高。因此，本研究将在UA的基础上进行优化，寻找具有更好活性的PDE2抑制剂。本研究以4HTX为靶蛋白，UA为先导化合物，以4HTX与BAY60-7550结合的晶体结构为参考，设计了一系列UA衍生物。经过彻底的筛选，我们成功地确定了8-羟基作为精确的修饰位点。以2-溴-5-羟基苯甲酸为主要原料，合成了一系列8-羟基修饰的UA。随后，我们使用磷酸二酯酶测定试剂盒评估了这些合成的UA衍生物的抑制活性。最终，我们总共筛选了34个衍生品；其中化合物1f、1q、2d和2j对PDE2具有显著的抑制活性，半峰抑制浓度分别为3.05 μM、0.67 μM、0.57 μM和4.96 μM。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.