Investigation of 2,3-diaryl-1,4-thiazolidin-4-ones as promising agents for reducing lipid accumulation in liver cell through AMPK activation: synthesis, in vitro, in silico and lipidomic studies

Abstract

1,3-Thiazolidin-4-ones are versatile heterocyclic scaffolds with diverse biological activities, however efficient synthesis and identification of potent lipid-lowering derivatives remain challenging. Here, we report a rapid, scalable sealed-tube, acid-catalyzed three-component synthesis of 2,3-diaryl-1,3-thiazolidin-4-ones, enabling broad substrate tolerance and the preparation of thirty synthetic derivatives, including twelve novel compounds, with moderate to excellent yields (from 25% to quantitative yield). Biological evaluation in HepG2 cells identified compound 4y as a non-toxic lead with superior lipid-lowering activity in both prophylactic and therapeutic oleic acid-induced steatosis models, comparable to the clinically used hepatoprotective agent silymarin. Mechanistic studies revealed that 4y robustly activates AMPKα, promoting lipid catabolism while suppressing lipogenesis, as confirmed by western blot, immunofluorescence, and molecular docking. Lipidomic profiling further demonstrated that 4y selectively reduces pathogenic ceramide and phosphatidylethanolamine species, highlighting its broad lipidome remodeling potential. These results establish 4y as a promising lead for the treatment of fatty liver disease and provide a practical synthetic platform for the development of thiazolidin-4-one-based metabolic therapeutics.