1. Discovery of a series of 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety as potent Escherichia coli β-glucuronidase inhibitors
- Author
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Bin Wei, Jin-Biao Yu, Zi-Ning Cui, Si-Jia Wang, Ya-Sheng Li, Lu-Lu He, Ao-Qi Du, Jing He, Zhen-Yi Zhou, Tao-Shun Zhou, Hong Wang, and Zhi-Kun Yang
- Subjects
Stereochemistry ,medicine.disease_cause ,Biochemistry ,Molecular Docking Simulation ,Structure-Activity Relationship ,chemistry.chemical_compound ,Furan ,Drug Discovery ,Escherichia coli ,medicine ,Moiety ,Furans ,Thiazole ,Molecular Biology ,Glucuronidase ,Glycoproteins ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Thiazoles ,Docking (molecular) ,Uncompetitive inhibitor - Abstract
Gut microbial β-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 β-glucuronidase (EcGUS). Twelve of them showed satisfactory inhibition against EcGUS with IC50 values ranging from 0.25 μM to 2.13 μM with compound 12 exhibited the best inhibition. Inhibition kinetics studies indicated that compound 12 (Ki = 0.14 ± 0.01 μM) 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.
- Published
- 2021