2,5-Disubstituted furan derivatives containing 1,3,4-thiadiazole moiety as potent α-glucosidase and E. coli β-glucuronidase inhibitors

Ya-Sheng Li; Min He; Tao-Shun Zhou; Qin Wang; Lulu He; Si-Jia Wang; Bei Hu; Bin Wei; Hong Wang; Zi-Ning Cui

doi:10.1016/j.ejmech.2021.113322

2,5-Disubstituted furan derivatives containing 1,3,4-thiadiazole moiety as potent α-glucosidase and E. coli β-glucuronidase inhibitors

Eur J Med Chem. 2021 Apr 15:216:113322. doi: 10.1016/j.ejmech.2021.113322. Epub 2021 Feb 23.

Authors

Ya-Sheng Li¹, Min He², Tao-Shun Zhou¹, Qin Wang³, Lulu He², Si-Jia Wang⁴, Bei Hu¹, Bin Wei⁵, Hong Wang⁶, Zi-Ning Cui⁷

Affiliations

¹ College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China.
² State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou, 510642, China.
³ Department of Endocrinology, The 903rd Hospital of PLA, Hangzhou, 310013, China.
⁴ College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China; Center for Human Nutrition, David Geffen School of Medicine, University of California, Los Angeles, CA, 90024, USA.
⁵ College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: binwei@zjut.edu.cn.
⁶ College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: hongw@zjut.edu.cn.
⁷ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China. Electronic address: ziningcui@scau.edu.cn.

PMID: 33652353
DOI: 10.1016/j.ejmech.2021.113322

Abstract

In this paper, the 2,5-disubstituted furan derivatives containing 1,3,4-thiadiazole were synthesized and screened for their inhibitory activity against α-glucosidase and β-glucuronidases to obtain potent α-glucosidase inhibitor 9 (IC₅₀ = 0.186 μM) and E. coli β-glucuronidase inhibitor 26 (IC₅₀ = 0.082 μM), respectively. The mechanisms of the compounds were studied. The kinetic study revealed that compound 9 is a competitive inhibitor against α-glucosidase (Ki = 0.05 ± 0.003 μM) and molecular docking simulation showed several key interactions between 9 and the target including hydrogen bond and p-π stacking interaction. Derivative 26 (Ki = 0.06 ± 0.005 μM) displayed uncompetitive inhibition behavior against EcGUS. Furthermore, the result of docking revealed the furan ring of 26 may be a key moiety in obstructing the active domain of EcGUS. In addition, compound 15 exhibited significant inhibitory activity against these two enzymes, with potential therapeutic effects against diabetes and against CPT-11-induced diarrhea. At the same time, their low toxicity against normal liver tissue LO2 cells lays the foundation for in vivo studies and the development of bifunctional drug.

Keywords: 1,3,4-Thiadiazole; 2,5-Disubstituted furan derivatives; CPT-11-Induced toxicity; Diabetes; E. coli β-glucuronidase; α-Glucosidase.

MeSH terms

Binding Sites
Catalytic Domain
Cell Line
Cell Survival
Escherichia coli / enzymology*
Escherichia coli Proteins / antagonists & inhibitors
Escherichia coli Proteins / metabolism
Furans / chemistry*
Furans / pharmacology
Glucuronidase / antagonists & inhibitors
Glucuronidase / metabolism
Glycoproteins / chemistry*
Glycoproteins / pharmacology
Glycoside Hydrolase Inhibitors / chemistry*
Glycoside Hydrolase Inhibitors / pharmacology
Humans
Kinetics
Molecular Docking Simulation
Structure-Activity Relationship
Thiadiazoles / chemistry*

Substances

Escherichia coli Proteins
Furans
Glycoproteins
Glycoside Hydrolase Inhibitors
Thiadiazoles
beta-glucuronidase inhibitor
1,3,4-thiadiazole
Glucuronidase