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

Design, synthesis of urolithin A, the metabolite of ellagitannins, and its biological activity of phosphodiesterase II (PDE2) inhibitors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Design, synthesis of urolithin A, the metabolite of ellagitannins, and its biological activity of phosphodiesterase II (PDE2) inhibitors Huanzhou Li, Feng Zhou, Qiulin Hu, Long Tang, Aibin Zheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7383061/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. Biological sciences/Biochemistry Biological sciences/Chemical biology Physical sciences/Chemistry Biological sciences/Drug discovery PDE2 inhibitors Urolithin A Molecular docking Chemical synthesis Bioactivity assay Full Text Additional Declarations No competing interests reported. Supplementary Files supporting.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7383061","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":523914971,"identity":"65857983-225a-43a5-9560-7d4d2cda4701","order_by":0,"name":"Huanzhou Li","email":"","orcid":"","institution":"Affiliated Changzhou Children's Hospital of Nantong University，","correspondingAuthor":false,"prefix":"","firstName":"Huanzhou","middleName":"","lastName":"Li","suffix":""},{"id":523914972,"identity":"906a4930-c774-470a-9591-e90299dbddb8","order_by":1,"name":"Feng Zhou","email":"","orcid":"","institution":"Changzhou 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