Design, synthesis, and biological evaluation of (thio)urea derivatives as potent Escherichia coli β-glucuronidase inhibitors

  • J Enzyme Inhib Med Chem. 2024 Dec;39(1):2387415. doi: 10.1080/14756366.2024.2387415.
Keren Xu  1 ,  Leyi Ying  1 ,  Titi Ying  1 ,  Qihao Wu  1  2 ,  Lin Du  3 ,  Yanlei Yu  1 ,  Youmin Ying  1 ,  Bin Wei  1  4 ,  Hong Wang  1 ,  Zhikun Yang  1  4
Affiliations
  • 1. College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou, China.
  • 2. Department of Chemistry, Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA.
  • 3. Ministry of Education & College of Agronomy and Biotechnology, China Agricultural University, Beijing, China.
  • 4. Binjiang Cyberspace Security Institute of Zhejiang University of Technology, Hangzhou, China.
PMID: 39140677 DOI: 10.1080/14756366.2024.2387415
Abstract

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.

Keywords
(thio)urea derivatives; gastrointestinal adverse events; structure-activity relationship; β-Glucuronidase inhibitor.
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