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

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.

SUBMITTER: Xu K 

PROVIDER: S-EPMC11328603 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature

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

Xu Keren K   Ying Leyi L   Ying Titi T   Wu Qihao Q   Du Lin L   Yu Yanlei Y   Ying Youmin Y   Wei Bin B   Wang Hong H   Yang Zhikun Z  

Journal of enzyme inhibition and medicinal chemistry 20240814 1

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> =  ...[more]

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