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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 38; no. 1; p. 2166937
• Main Authors: Li, Aiyun, Guan, Li, Su, Wanzhen, Zhao, Ning, Song, Xuwen, Wang, Jin, Tang, Xiaoxiao, Li, Weize, Jiao, Xiangying
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.12.2023; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Apoptosis; Beta cells; Carrier Proteins - metabolism; Carrier Proteins - pharmacology; Cell injury; Cell Line; Cell viability; Chromatography; Design; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetic neuropathy; Drugs; Fatty acids; Humans; Hyperglycemia; Inflammasomes; Inflammasomes - metabolism; Inflammasomes - pharmacology; Inflammation; Insulin resistance; Intracellular signalling; Nitrogen; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Obesity; Oxidative Stress; oxidative stress and inflammation; Palmitic acid; pancreatic β cell apoptosis; Pharmacy; Physiology; Proteins; Quinazoline derivatives; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research Paper; T2DM; Therapeutic targets; Thioredoxin; TXNIP inhibition; T2DM; oxidative stress and inflammation; pancreatic β cell apoptosis; TXNIP inhibition; Quinazoline derivatives
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2023.2166937

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.