2. Academic Validation
  3. Design and synthesis of N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide-based α-glucosidase inhibitors

Design and synthesis of N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide-based α-glucosidase inhibitors

  • Bioorg Med Chem Lett. 2025 Mar 1:117:130068. doi: 10.1016/j.bmcl.2024.130068.
Yi-Tong Chen 1,  Bo-Wen Wan 1,  Kai-Ming Wang 1,  Kong-Kai Zhu 2,  Ning Meng 3,  Cheng-Shi Jiang 4,  Juan Zhang 5
Affiliations

Affiliations

  • 1 School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
  • 2 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 3 School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: mls_mengn@ujn.edu.cn.
  • 4 School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: jiangchengshi-20@163.com.
  • 5 School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: bio_zhangj@ujn.edu.cn.
PMID: 39662707 DOI: 10.1016/j.bmcl.2024.130068
Abstract

This study investigates the design and synthesis of a series of novel selective α-glucosidase inhibitors based on N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide framework, employing a bioisosterism strategy. Among the nineteen newly synthesized analogs, compound 4d9 demonstrated the highest α-glucosidase inhibitory potency (IC50 = 2.11 μM) when compared to the established inhibitors Acarbose (IC50 = 327.0 μM) and HXH8r (IC50 = 15.32 μM), while exhibiting a remarkable 17.48-fold selectivity for α-glucosidase over α-amylase. Kinetic studies revealed that compound 4d9 acts as a non-competitive inhibitor, and its binding interactions were further investigated using molecular docking analysis. Additionally, compound 4d9 showed noncytotoxic effects on human normal hepatocyte (LO2) cells and demonstrated improved metabolic stability in rat plasma. These findings position compound 4d9 as a promising candidate for the development of therapeutics targeting type 2 diabetes.

Keywords

Molecular docking; N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide; Non-competitive inhibitor; Type 2 diabetes; α-Glucosidase inhibitors.

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