TXNIP inhibition in the treatment of type 2 diabetes mellitus: design, synthesis, and biological evaluation of quinazoline derivatives.
J Enzyme Inhib Med Chem
; 38(1): 2166937, 2023 Dec.
Article
in En
| MEDLINE
| ID: mdl-36651294
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 ß cell injury. In vitro cell viability assay showed that compounds D-2 and C-1 could effectively protect ß 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 ß cell protective agents to inhibit TXNIP expression and might serve as promising lead candidates for the treatment of T2DM.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetes Mellitus, Type 2
/
NLR Family, Pyrin Domain-Containing 3 Protein
Limits:
Humans
Language:
En
Journal:
J Enzyme Inhib Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2023
Document type:
Article