Design, synthesis and biological evaluation of novel quinolinone derivatives as potential hypoglycemic agents with hepatorenal protective effects.

Promoting glucose utilization is a pivotal strategy for reducing blood glucose, which primarily involves directly enhancing tissue uptake and consumption to effectively clear circulating glucose. Based on the promising lead compound S6 developed in our laboratory, a series of 42 quinolinone derivatives were synthesized and systematically screened for their ability to promote glucose consumption in HepG2 cells. Among these derivatives, the optimized compound 4 f exhibited potent hypoglycemic activity, increasing glucose consumption by 61% in HepG2 cells compared to the control. Further studies demonstrated that compound 4 f showed negligible cytotoxicity in both HepG2 and 3T3-L1 cells at 200 μM, along with favorable metabolic stability in mouse liver microsomes and plasma. In vivo experiments revealed that 4 f dose-dependently reduced blood glucose levels in glucose-challenged C57BL/6 J mice and effectively lowered hyperglycemia in db/db diabetic mice, while also ameliorating liver and kidney impairment. Additionally, mechanistic investigation suggested that the hypoglycemic effect of 4 f is mediated through activation of the AMPK pathway. These findings demonstrate that compound 4 f is a molecule possessing hypoglycemic, low toxicity, and hepatorenal protective effects, positioning it as a promising novel scaffold antidiabetic candidate worthy of further development.