Synthesis, biological evaluation, and molecular docking study of novel allyl-retrochalcones as a new class of protein tyrosine phosphatase 1B inhibitors

• Published in: Bioorganic & medicinal chemistry 2019-03, Vol.27 (6), p.963-977
• Main Authors: Zhao, Yunjie, Cao, Yongkai, Chen, Huizhen, Zhuang, Fei, Wu, Chao, Yoon, Goo, Zhu, Weiwei, Su, Ying, Zheng, Suqing, Liu, Zhiguo, Cheon, Seung Hoon
• Format: Article
• Language: English
• Subjects: Allyl Compounds - chemical synthesis; Allyl Compounds - chemistry; Allyl Compounds - pharmacology; Allyl-retrochalcone; Animals; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Drug design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hep G2 Cells; Humans; Male; Mice; Molecular Docking Simulation; Protein tyrosine phosphatase 1B; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Quantitative Structure-Activity Relationship; Rats, Sprague-Dawley; Structure-activity relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.01.034

[Display omitted] We describe herein the design, synthesis, and biological evaluation of a series of novel protein tyrosine phosphatase 1B (PTP1B) inhibitor retrochalcones having an allyl chain at the C-5 position of their B ring. Biological screening results showed that the majority of these compounds exhibited an inhibitory activity against PTP1B. Thus, preliminary structure-activity relationship (SAR) and quantitative SAR analyses were conducted. Among the compounds, 23 was the most potent inhibitor, exhibiting the highest in vitro inhibitory activity against PTP1B with an IC50 of 0.57 µM. Moreover, it displayed a significant hepatoprotective property via activation of the IR pathway in type 2 diabetic db/db mice. In addition, the results of our docking study showed that 23, as a specific inhibitor of PTP1B, effectively transformed the WPD loop from “close” to “open” in the active site. These results may reveal suitable compounds for the development of PTP1B inhibitors.