Discovery of a series of 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety as potent Escherichia coli β-glucuronidase inhibitors

Gut microbial beta-glucuronidases have drawn much attention due to their role as a potential therapeutic target to alleviate some drugs or their metabolites-induced gastrointestinal toxicity. In this study, fifteen 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety (1-15) were synthesized and evaluated for their inhibitory effects against Escherichia coli beta-glucuronidase (EcGUS). Twelve of them showed satisfactory inhibition against EcGUS with IC50 values ranging from 0.25 mu M to 2.13 mu M with compound 12 exhibited the best inhibition. Inhibition kinetics studies indicated that compound 12 (K-i = 0.14 +/- 0.01 mu M) was an uncompetitive inhibitor for EcGUS and molecular docking simulation further predicted the binding model and capability of compound 12 with EcGUS. A preliminary structure-inhibitory activity relationship study revealed that the heterocyclic backbone and bromine substitution of benzene may be essential for inhibition against EcGUS. The compounds have the potential to be applied in drug-induced gastrointestinal toxicity and the findings would help researchers to design and develop more effective 5-phenyl-2-furan type EcGUS inhibitors.

Automated summary

Fifteen 5-phenyl-2-furan derivatives were synthesized and evaluated for their inhibitory effects against Escherichia coli beta-glucuronidase (EcGUS), with twelve of them showing satisfactory inhibition. Compound 12 exhibited the best inhibition and was found to be an uncompetitive inhibitor for EcGUS. The molecular docking simulation further predicted the binding model and capability of compound 12 with EcGUS.