Thiazolidin-2-cyanamides derivatives as novel potent Escherichia coli β-glucuronidase inhibitors and their structure-inhibitory activity relationships

• Main Authors: Tao-Shun Zhou (Author), Bin Wei (Author), Min He (Author), Ya-Sheng Li (Author), Ya-Kun Wang (Author), Si-Jia Wang (Author), Jian-Wei Chen (Author), Hua-Wei Zhang (Author), Zi-Ning Cui (Author), Hong Wang (Author)
• Format: Book
• Published: Taylor & Francis Group, 2020-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1475-6366; 1475-6374; 10.1080/14756366.2020.1816998
• Keywords: structure-inhibitory activity relationships; thiazolidin-2-cyanamide derivatives; escherichia coli β-glucuronidase; β-glucuronidase inhibitors; cpt-11-induced toxicity; Therapeutics. Pharmacology; RM1-950
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 1736-1742 (2020)

Gut microbial β-glucuronidases have the ability to deconjugate glucuronides of some drugs, thus have been considered as an important drug target to alleviate the drug metabolites-induced gastrointestinal toxicity. In this study, thiazolidin-2-cyanamide derivatives containing 5-phenyl-2-furan moiety (1-13) were evaluated for inhibitory activity against Escherichia coli β-glucuronidase (EcGUS). All of them showed more potent inhibition than a commonly used positive control, d-saccharic acid 1,4-lactone, with the IC50 values ranging from 1.2 µM to 23.1 µM. Inhibition kinetics studies indicated that compound 1-3 were competitive type inhibitors for EcGUS. Molecular docking studies were performed and predicted the potential molecular determinants for their potent inhibitory effects towards EcGUS. Structure-inhibitory activity relationship study revealed that chloro substitution on the phenyl moiety was essential for EcGUS inhibition, which would help researchers to design and develop more effective thiazolidin-2-cyanamide type inhibitors against EcGUS.