Cinnamic acid derivatives: inhibitory activity against Escherichia coli β-glucuronidase and structure–activity relationships

Abstract

Gut microbial β-glucuronidase (GUS) is a potential therapeutic target to reduce gastrointestinal toxicity caused by irinotecan. In this study, the inhibitory effects of 17 natural cinnamic acid derivatives on Escherichia coli GUS (EcGUS) were characterised. Seven compounds, including caffeic acid ethyl ester (CAEE), had a stronger inhibitory effect (IC₅₀ = 3.2–22.2 µM) on EcGUS than the positive control, D-glucaric acid-1,4-lactone. Inhibition kinetic analysis revealed that CAEE acted as a competitive inhibitor. The results of molecular docking analysis suggested that CAEE bound to the active site of EcGUS through interactions with Asp163, Tyr468, and Glu504. In addition, structure–activity relationship analysis revealed that the presence of a hydrogen atom at R₁ and bulky groups at R₉ in cinnamic acid derivatives was essential for EcGUS inhibition. These data are useful to design more potent cinnamic acid-type inhibitors of EcGUS.

Keywords:

• Cinnamic acid derivatives
• docking
• Escherichia coli
• β-glucuronidase
• structure–activity relationship

Acknowledgement

The authors thank Prof. Yan Ru (University of Macau, Macau, China) for providing us the recombinant E. coli BL21(DE3) for Escherichia coli β-glucuronidase preparation.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant number 81502941].