Serious hepatic and cardiovascular complications after the treatment with thiazolidinediones (TZDs) class of insulin sensitizers have significantly retarded the advancement of new TZD-based peroxisome proliferator activated receptor agonists that bind with high affinity and selectivity. The aim of the present study is to design new antihyperglycemic agents that promote insulin sensitivity through partial adipogenesis as well as demonstrate beneficial hepatoprotective activity. The results indicated that among forty screened compounds, three of the novel pyranones at a dose of 10 µM increased the preadipocyte differentiation into adipocytes in 3T3L1 cell lines. They showed insulin-sensitizing effect by significantly increasing the glucose uptake and exhibited insulin resistance reversal. These compounds at a dose of 20 mg/kg significantly protected against thioacetamide-induced hepatotoxic changes in the serum biochemistry (p<0.05) as compared to standard hepatoprotectant silymarin and also ameliorated the histopathological alterations in the liver tissues after acute liver injury in swiss mice.