Keren Xu, Leyi Ying, Titi Ying, Qihao Wu, Lin Du, Yanlei Yu, Youmin Ying, Bin Wei, Hong Wang, Zhikun Yang
{"title":"作为强效大肠杆菌β-葡糖醛酸酶抑制剂的(硫代)脲衍生物的设计、合成和生物学评价。","authors":"Keren Xu, Leyi Ying, Titi Ying, Qihao Wu, Lin Du, Yanlei Yu, Youmin Ying, Bin Wei, Hong Wang, Zhikun Yang","doi":"10.1080/14756366.2024.2387415","DOIUrl":null,"url":null,"abstract":"<p><p>EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that <b>E-9</b> (IC<sub>50</sub> = 2.68 μM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC<sub>50</sub> = 45.8 μM). Additionally, the inhibitory kinetic study indicated that <b>E-9</b> (K<sub>i</sub> = 1.64 μM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the <i>para</i>-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that <b>E-9</b> has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that <b>E-9</b> could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2387415"},"PeriodicalIF":5.6000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328603/pdf/","citationCount":"0","resultStr":"{\"title\":\"Design, synthesis, and biological evaluation of (thio)urea derivatives as potent <i>Escherichia coli β</i>-glucuronidase inhibitors.\",\"authors\":\"Keren Xu, Leyi Ying, Titi Ying, Qihao Wu, Lin Du, Yanlei Yu, Youmin Ying, Bin Wei, Hong Wang, Zhikun Yang\",\"doi\":\"10.1080/14756366.2024.2387415\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that <b>E-9</b> (IC<sub>50</sub> = 2.68 μM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC<sub>50</sub> = 45.8 μM). Additionally, the inhibitory kinetic study indicated that <b>E-9</b> (K<sub>i</sub> = 1.64 μM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the <i>para</i>-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that <b>E-9</b> has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that <b>E-9</b> could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"39 1\",\"pages\":\"2387415\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328603/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2024.2387415\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/14 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2024.2387415","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/14 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Design, synthesis, and biological evaluation of (thio)urea derivatives as potent Escherichia coli β-glucuronidase inhibitors.
EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that E-9 (IC50 = 2.68 μM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC50 = 45.8 μM). Additionally, the inhibitory kinetic study indicated that E-9 (Ki = 1.64 μM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the para-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that E-9 has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that E-9 could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.
期刊介绍:
Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents.
Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research.
The journal’s focus includes current developments in:
Enzymology;
Cell biology;
Chemical biology;
Microbiology;
Physiology;
Pharmacology leading to drug design;
Molecular recognition processes;
Distribution and metabolism of biologically active compounds.