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

Tao-Shun Zhou; Lu-Lu He; Jing He; Zhi-Kun Yang; Zhen-Yi Zhou; Ao-Qi Du; Jin-Biao Yu; Ya-Sheng Li; Si-Jia Wang; Bin Wei; Zi-Ning Cui; Hong Wang

doi:10.1016/j.bioorg.2021.105306

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

Bioorg Chem. 2021 Nov:116:105306. doi: 10.1016/j.bioorg.2021.105306. Epub 2021 Aug 27.

Authors

Tao-Shun Zhou¹, Lu-Lu He², Jing He¹, Zhi-Kun Yang³, Zhen-Yi Zhou¹, Ao-Qi Du¹, Jin-Biao Yu¹, Ya-Sheng Li¹, Si-Jia Wang⁴, Bin Wei⁵, Zi-Ning Cui⁶, Hong Wang⁷

Affiliations

¹ College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
² State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Lingnan Guangdong Laboratory of Modern Agriculture, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.
³ College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China; Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China.
⁴ College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China; Center for Human Nutrition, David Geffen School of Medicine, University of California, Rehabilitation Building 32-21, 1000 Veteran Avenue, Los Angeles, CA 90024, USA.
⁵ College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China. Electronic address: binwei@zjut.edu.cn.
⁶ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Lingnan Guangdong Laboratory of Modern Agriculture, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China. Electronic address: zinningcui@scau.edu.cn.
⁷ College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China. Electronic address: hongw@zjut.edu.cn.

PMID: 34521047
DOI: 10.1016/j.bioorg.2021.105306

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 (K_i = 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.

Keywords: 1,3-thiazole moiety; 5-phenyl-2-furan derivatives; Docking; Structure-inhibitory activity relationship; β-glucuronidase inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Escherichia coli / enzymology*
Furans / chemical synthesis
Furans / chemistry
Furans / pharmacology*
Glucuronidase / antagonists & inhibitors*
Glucuronidase / metabolism
Glycoproteins / chemical synthesis
Glycoproteins / chemistry
Glycoproteins / pharmacology*
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Furans
Glycoproteins
Thiazoles
beta-glucuronidase inhibitor
Glucuronidase