TXNIP inhibition in the treatment of type 2 diabetes mellitus: design, synthesis, and biological evaluation of quinazoline derivatives

Abstract

Thioredoxin interacting protein (TXNIP) is a potential drug target for type 2 diabetes mellitus (T2DM) treatment. A series of quinazoline derivatives were designed, synthesised, and evaluated to inhibit TXNIP expression and protect from palmitate (PA)-induced β cell injury. In vitro cell viability assay showed that compounds D-2 and C-1 could effectively protect β cell from PA-induced apoptosis, and subsequent results showed that these two compounds decreased TXNIP expression by accelerating its protein degradation. Mechanistically, compounds D-2 and C-1 reduced intracellular reactive oxygen species (ROS) production and modulated TXNIP-NLRP3 inflammasome signalling, and thus alleviating oxidative stress injury and inflammatory response under PA insult. Besides, these two compounds were predicted to possess better drug-likeness properties using SwissADME. The present study showed that compounds D-2 and C-1, especially compound D-2, were potent pancreatic β cell protective agents to inhibit TXNIP expression and might serve as promising lead candidates for the treatment of T2DM.

Keywords:

• Quinazoline derivatives
• TXNIP inhibition
• oxidative stress and inflammation
• pancreatic β cell apoptosis
• T2DM

Acknowledgement

Thanks for the support of Shanxi Key Subjects Construction (FSKSC), and Shanxi “1331 Project” Key Subjects Construction.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was financially supported by the Youth Project of Applied Basic Research Program in Shanxi Province (202103021223212); Science Research Start-up Foundation for Doctor of Shanxi Medical University (XD2012); National Natural Science Foundation of China (82004075); Shaanxi University Youth Innovation Team Construction Funding Project (Shaanxi Education [2019] No.90); Xi’an Medical University Science and Technology Innovation Team Support (2021TDPT04); Innovation and Entrepreneurship Training Program for College Students of Xi’an Medical University (121522082); and Project of Shaanxi Provincial Science and Technology Department (2023-JC-QN-0827).